Maternal Uniparental Disomy for Chromosome 20: Physical and Endocrinological Characteristics of Five Patients

Maternal Uniparental Disomy for Chromosome 20: Physical and Endocrinological Characteristics of... Abstract Context Maternal uniparental disomy for chromosome 20 [UPD(20)mat], resulting in aberrant expression of imprinted transcripts at the GNAS locus, is a poorly characterized condition. These patients manifested a phenotype similar to that of Silver-Russell syndrome (SRS) and small for gestational age-short stature (SGA-SS); however, the etiological relationship between UPD(20)mat and SRS/SGA-SS remains unclear. Moreover, no report has described endocrinological assessment of UPD(20)mat patients, although paternal UPD(20), the mirror image entity of UPD(20)mat, is known to cause multiple hormone resistance reflecting reduced α-subunit of the stimulatory G protein expression. Participants Patients 1 to 5 showed nonmosaic heterodisomy and/or isodisomy for the entire chromosome 20. Patients 1 to 3 and 4 were identified through UPD(20)mat screening for 55 patients with etiology-unknown SRS and 96 patients with SGA-SS, respectively. Patient 5 was identified through molecular analysis for patients with developmental defects. Patients 1 to 5 manifested postnatal growth failure and feeding problems, with or without developmental delay, and other clinical features. Patients 1 to 4 were born SGA. Patients 4 and 5 exhibited hypercalcemia and low or low-normal parathyroid hormone levels. Patient 1 showed constantly decreased thyroid-stimulating hormone (TSH) levels after 12 years of age, although she had a normal TSH level at 5.2 years of age. Conclusion The results suggest that UPD(20)mat underlies growth failure and feeding problems with additional features and could account for >5% of etiology-unknown SRS and small percentages of SGA-SS. Most important, this study provides an indication that UPD(20)mat can be associated with hypersensitivity of hormone receptors, which may gradually develop with age. The guanine nucleotide binding protein, alpha stimulating (GNAS) locus on 20q13 encompasses several imprinted transcripts, including α-subunit of the stimulatory G protein (Gsα), extra large form of Gsα (XLαs), and A/B (1). Of these, Gsα is expressed in the proximal renal tubule, thyroid, pituitary, and ovary, predominantly from the maternally derived allele (1), whereas XLαs and A/B are expressed in various tissues primarily from the paternally derived allele (1). Gsα regulates the cyclic adenosine monophosphate-mediated signaling cascade of the receptors of parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), growth hormone (GH)-releasing hormone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) (1). Consequently, paternal uniparental disomy for chromosome 20 causes multiple hormone resistance, reflecting reduced Gsα expression (2). Paternal uniparental disomy for chromosome 20 typically results in pseudohypoparathyroidism and hypothyroidism and accounts for ∼10% of patients with sporadic pseudohypoparathyroidism type 1b (2). In contrast, maternal uniparental disomy for chromosome 20 [UPD(20)mat], particularly UPD(20)mat without trisomy mosaicism, is a poorly characterized condition; only 10 nonmosaic cases have been studied clinically (3, 4). These patients presented with pre- and postnatal growth failure and feeding difficulties. Although the phenotypes of these cases overlapped with that of Silver-Russell syndrome (SRS) and small for gestational age-short stature (SGA-SS) (3, 4), the etiological relationship between UPD(20)mat and SRS/SGA-SS remains uncertain. Moreover, there has been no report of endocrinological assessment of UPD(20)mat patients, except for measurements of basal GH and insulinlike growth factor 1 (IGF-1) levels in some patients. Case Reports Patients 1 to 5 were unrelated Japanese children with nonmosaic UPD(20)mat. Patients 1 to 3 and 4 were identified through DNA methylation analyses for the GNAS locus in 55 patients with SRS of unknown etiology and in 96 patients with SGA-SS, respectively (Supplemental Methods). Patient 5 was identified through molecular analysis for patients with developmental delay and severe growth failure. Comparative genomic hybridization + single nucleotide polymorphism microarray and microsatellite analyses revealed that patients 1 to 5 had maternal UPD for the entire chromosome 20 (Supplemental Fig. 1 and Supplemental Table 1). Patient 1 had full isodisomy, whereas the other patients exhibited isodisomy and heterodisomy. Physical examination findings Patients 1 to 5 exhibited postnatal growth failure, and patients 1 to 4 were born SGA (Table 1, Fig. 1, and Supplemental Table 2). The birth weight, length, and occipitofrontal circumferences (OFCs) of UPD(20)mat patients were larger than those of the other participants with SRS or SGA-SS. The standard deviation scores (SDSs) of the present OFCs were similar to those of the birth OFCs in most UPD(20)mat patients. The SDSs of the present OFCs of UPD(20)mat were significantly larger than those of other participants with SGA-SS. Bone age was delayed in all school-aged patients. GH treatment yielded a good response in patient 2 but not in patient 1 (Fig. 1). Hypoplastic placenta and oligohydramnios were detected in most patients. All of the patients showed feeding difficulties and/or low body mass index (BMI) at 2 years of age. Patients 1 and 3 required gastrostomy or tube feeding for >2 years after birth. Patients 1 to 3 satisfied the diagnostic criteria of the Netchine-Harbison clinical scoring system for SRS (4). Triangular face was present in four patients (Table 1 and Fig. 1). Developmental delay, with or without hypotonia, was observed in three patients. One of three school-aged patients attended a special educational program, whereas the others showed normal achievement in elementary schools. Table 1. Clinical Manifestations of Our Patients and Previously Reported Cases Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Previous Reportsa  Uniparental Disomy Type  Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy    Sex  Female  Male  Female  Female  Male  Male:Female = 5:4  Age at last evaluation, y:mo  15:1  10:9  07:10  2:2  2:4  6 (0:3 ∼ 12)  Pregnancy and delivery               Gestational age, wk  36  34  37  37  36  38 (36 ∼ 39)   Placental weight  235 g  Small  NA  NA  Small     Oligohydramnios  +  +  +  +  −     Paternal age at childbirth, y  35  28  37  39  42     Maternal age at childbirth, yb  33  28  42  41  39  38 (30 ∼ 43)  Growth               Birth length, cm (SDS)  39.0 (–2.7)  40.3 (–1.6)  44.4 (–1.4)  42.6 (–2.3)  47.0 (0.2)     Birth weight, g (SDS)  1252 (–4.1)  1354 (–2.8)  2000 (–1.9)  1935 (–2.2)  2110 (–1.5)  Second percentile (<second ∼ <fifth)   Birth OFC, cm (SDS)  29.5 (–1.7)  29.0 (–1.1)  30.0 (–1.9)  31.2 (–1.2)  30.5 (–1.2)     Present height, cm (SDS)  138.4 (–3.5)  141.6 (0.2)  111.0 (–2.4)  75.3 (–3.5)  77.2 (–3.5)  Fifth percentile (<second ∼ 10th)   Present weight, kg (SDS)  26.4 (–3.0)  26.8 (–1.1)  14.1 (–2.3)  6.7 (–3.9)  8.1 (–3.2)  Fifth percentile (<second ∼ 75th)   Present BMI (SDS)  13.78 (–3.9)  13.37 (–2.7)  11.44 (–3.8)  11.85 (–3.4)  13.59 (–2.0)     Present OFC, cm (SDS)  53.1 (–1.5)  50.7 (–1.8)  49 (–2.0)  45.4 (–1.3)  50.0 (0.7)     Tanner stage at present  Breast 3, Pubic hair 1  NA  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1     GH treatment  +  +  −  −  −  4/9  Development               Hypotonia  −  −  −  +  +     IQ/DQ  IQ 78  DQ 113  NE  DQ 65  DQ 75    Other findings               Feeding difficulties  +  −  +  +  +     Tube feeding or gastrostoma  Gastrostoma (∼10 y)  −  −  Tube feeding (ongoing)  −  6/9   Triangular face  +  −  +  +  +     Abnormalities in the bone structures of the hands and wrists  −  −  −  −  −     Extra features  GER, dermal sinus      Face asymmetry, right low-set ear, scoliosis      Netchine-Harbison scoring system features for SRS               Birth length and/or weight ≤ −2 SDS  +  +  −  +  −     Relative macrocephaly at birthc  +  +  −  −  −     Postnatal height (at 2 y) ≤ −2 SDS  +  +  +  +  +     Prominent forehead (1–3 years)  −  +  +  −  +     Body asymmetry  −  −  +  −  −     Feeding difficulties and/or low BMId  +  +  +  +  +    Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Previous Reportsa  Uniparental Disomy Type  Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy    Sex  Female  Male  Female  Female  Male  Male:Female = 5:4  Age at last evaluation, y:mo  15:1  10:9  07:10  2:2  2:4  6 (0:3 ∼ 12)  Pregnancy and delivery               Gestational age, wk  36  34  37  37  36  38 (36 ∼ 39)   Placental weight  235 g  Small  NA  NA  Small     Oligohydramnios  +  +  +  +  −     Paternal age at childbirth, y  35  28  37  39  42     Maternal age at childbirth, yb  33  28  42  41  39  38 (30 ∼ 43)  Growth               Birth length, cm (SDS)  39.0 (–2.7)  40.3 (–1.6)  44.4 (–1.4)  42.6 (–2.3)  47.0 (0.2)     Birth weight, g (SDS)  1252 (–4.1)  1354 (–2.8)  2000 (–1.9)  1935 (–2.2)  2110 (–1.5)  Second percentile (<second ∼ <fifth)   Birth OFC, cm (SDS)  29.5 (–1.7)  29.0 (–1.1)  30.0 (–1.9)  31.2 (–1.2)  30.5 (–1.2)     Present height, cm (SDS)  138.4 (–3.5)  141.6 (0.2)  111.0 (–2.4)  75.3 (–3.5)  77.2 (–3.5)  Fifth percentile (<second ∼ 10th)   Present weight, kg (SDS)  26.4 (–3.0)  26.8 (–1.1)  14.1 (–2.3)  6.7 (–3.9)  8.1 (–3.2)  Fifth percentile (<second ∼ 75th)   Present BMI (SDS)  13.78 (–3.9)  13.37 (–2.7)  11.44 (–3.8)  11.85 (–3.4)  13.59 (–2.0)     Present OFC, cm (SDS)  53.1 (–1.5)  50.7 (–1.8)  49 (–2.0)  45.4 (–1.3)  50.0 (0.7)     Tanner stage at present  Breast 3, Pubic hair 1  NA  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1     GH treatment  +  +  −  −  −  4/9  Development               Hypotonia  −  −  −  +  +     IQ/DQ  IQ 78  DQ 113  NE  DQ 65  DQ 75    Other findings               Feeding difficulties  +  −  +  +  +     Tube feeding or gastrostoma  Gastrostoma (∼10 y)  −  −  Tube feeding (ongoing)  −  6/9   Triangular face  +  −  +  +  +     Abnormalities in the bone structures of the hands and wrists  −  −  −  −  −     Extra features  GER, dermal sinus      Face asymmetry, right low-set ear, scoliosis      Netchine-Harbison scoring system features for SRS               Birth length and/or weight ≤ −2 SDS  +  +  −  +  −     Relative macrocephaly at birthc  +  +  −  −  −     Postnatal height (at 2 y) ≤ −2 SDS  +  +  +  +  +     Prominent forehead (1–3 years)  −  +  +  −  +     Body asymmetry  −  −  +  −  −     Feeding difficulties and/or low BMId  +  +  +  +  +    Abbreviations: GER, gastroesophageal reflex; IQ/DQ, intellectual/developmental quotient; NA, not available; NE, not examined; a See Mulchandani et al. (3). b Patients 1 to 5 were born in 2002, 2006, 2009, 2015, and 2015, respectively. The average Japanese maternal ages were 29.8 years of age in 2002, 30.5 in 2006, 31.0 in 2009, and 31.3 in 2015. The average Japanese maternal ages were based on the annual nationwide survey data from the Ministry of Health, Labor, and Welfare (http://www.mhlw.go.jp/toukei/list/81-1.html). c Birth OFC SDS ≥ 1.5 above birth length or weight SDS. d BMI ≤ −2 SDS at 2 years. View Large Table 1. Clinical Manifestations of Our Patients and Previously Reported Cases Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Previous Reportsa  Uniparental Disomy Type  Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy    Sex  Female  Male  Female  Female  Male  Male:Female = 5:4  Age at last evaluation, y:mo  15:1  10:9  07:10  2:2  2:4  6 (0:3 ∼ 12)  Pregnancy and delivery               Gestational age, wk  36  34  37  37  36  38 (36 ∼ 39)   Placental weight  235 g  Small  NA  NA  Small     Oligohydramnios  +  +  +  +  −     Paternal age at childbirth, y  35  28  37  39  42     Maternal age at childbirth, yb  33  28  42  41  39  38 (30 ∼ 43)  Growth               Birth length, cm (SDS)  39.0 (–2.7)  40.3 (–1.6)  44.4 (–1.4)  42.6 (–2.3)  47.0 (0.2)     Birth weight, g (SDS)  1252 (–4.1)  1354 (–2.8)  2000 (–1.9)  1935 (–2.2)  2110 (–1.5)  Second percentile (<second ∼ <fifth)   Birth OFC, cm (SDS)  29.5 (–1.7)  29.0 (–1.1)  30.0 (–1.9)  31.2 (–1.2)  30.5 (–1.2)     Present height, cm (SDS)  138.4 (–3.5)  141.6 (0.2)  111.0 (–2.4)  75.3 (–3.5)  77.2 (–3.5)  Fifth percentile (<second ∼ 10th)   Present weight, kg (SDS)  26.4 (–3.0)  26.8 (–1.1)  14.1 (–2.3)  6.7 (–3.9)  8.1 (–3.2)  Fifth percentile (<second ∼ 75th)   Present BMI (SDS)  13.78 (–3.9)  13.37 (–2.7)  11.44 (–3.8)  11.85 (–3.4)  13.59 (–2.0)     Present OFC, cm (SDS)  53.1 (–1.5)  50.7 (–1.8)  49 (–2.0)  45.4 (–1.3)  50.0 (0.7)     Tanner stage at present  Breast 3, Pubic hair 1  NA  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1     GH treatment  +  +  −  −  −  4/9  Development               Hypotonia  −  −  −  +  +     IQ/DQ  IQ 78  DQ 113  NE  DQ 65  DQ 75    Other findings               Feeding difficulties  +  −  +  +  +     Tube feeding or gastrostoma  Gastrostoma (∼10 y)  −  −  Tube feeding (ongoing)  −  6/9   Triangular face  +  −  +  +  +     Abnormalities in the bone structures of the hands and wrists  −  −  −  −  −     Extra features  GER, dermal sinus      Face asymmetry, right low-set ear, scoliosis      Netchine-Harbison scoring system features for SRS               Birth length and/or weight ≤ −2 SDS  +  +  −  +  −     Relative macrocephaly at birthc  +  +  −  −  −     Postnatal height (at 2 y) ≤ −2 SDS  +  +  +  +  +     Prominent forehead (1–3 years)  −  +  +  −  +     Body asymmetry  −  −  +  −  −     Feeding difficulties and/or low BMId  +  +  +  +  +    Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Previous Reportsa  Uniparental Disomy Type  Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy    Sex  Female  Male  Female  Female  Male  Male:Female = 5:4  Age at last evaluation, y:mo  15:1  10:9  07:10  2:2  2:4  6 (0:3 ∼ 12)  Pregnancy and delivery               Gestational age, wk  36  34  37  37  36  38 (36 ∼ 39)   Placental weight  235 g  Small  NA  NA  Small     Oligohydramnios  +  +  +  +  −     Paternal age at childbirth, y  35  28  37  39  42     Maternal age at childbirth, yb  33  28  42  41  39  38 (30 ∼ 43)  Growth               Birth length, cm (SDS)  39.0 (–2.7)  40.3 (–1.6)  44.4 (–1.4)  42.6 (–2.3)  47.0 (0.2)     Birth weight, g (SDS)  1252 (–4.1)  1354 (–2.8)  2000 (–1.9)  1935 (–2.2)  2110 (–1.5)  Second percentile (<second ∼ <fifth)   Birth OFC, cm (SDS)  29.5 (–1.7)  29.0 (–1.1)  30.0 (–1.9)  31.2 (–1.2)  30.5 (–1.2)     Present height, cm (SDS)  138.4 (–3.5)  141.6 (0.2)  111.0 (–2.4)  75.3 (–3.5)  77.2 (–3.5)  Fifth percentile (<second ∼ 10th)   Present weight, kg (SDS)  26.4 (–3.0)  26.8 (–1.1)  14.1 (–2.3)  6.7 (–3.9)  8.1 (–3.2)  Fifth percentile (<second ∼ 75th)   Present BMI (SDS)  13.78 (–3.9)  13.37 (–2.7)  11.44 (–3.8)  11.85 (–3.4)  13.59 (–2.0)     Present OFC, cm (SDS)  53.1 (–1.5)  50.7 (–1.8)  49 (–2.0)  45.4 (–1.3)  50.0 (0.7)     Tanner stage at present  Breast 3, Pubic hair 1  NA  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1     GH treatment  +  +  −  −  −  4/9  Development               Hypotonia  −  −  −  +  +     IQ/DQ  IQ 78  DQ 113  NE  DQ 65  DQ 75    Other findings               Feeding difficulties  +  −  +  +  +     Tube feeding or gastrostoma  Gastrostoma (∼10 y)  −  −  Tube feeding (ongoing)  −  6/9   Triangular face  +  −  +  +  +     Abnormalities in the bone structures of the hands and wrists  −  −  −  −  −     Extra features  GER, dermal sinus      Face asymmetry, right low-set ear, scoliosis      Netchine-Harbison scoring system features for SRS               Birth length and/or weight ≤ −2 SDS  +  +  −  +  −     Relative macrocephaly at birthc  +  +  −  −  −     Postnatal height (at 2 y) ≤ −2 SDS  +  +  +  +  +     Prominent forehead (1–3 years)  −  +  +  −  +     Body asymmetry  −  −  +  −  −     Feeding difficulties and/or low BMId  +  +  +  +  +    Abbreviations: GER, gastroesophageal reflex; IQ/DQ, intellectual/developmental quotient; NA, not available; NE, not examined; a See Mulchandani et al. (3). b Patients 1 to 5 were born in 2002, 2006, 2009, 2015, and 2015, respectively. The average Japanese maternal ages were 29.8 years of age in 2002, 30.5 in 2006, 31.0 in 2009, and 31.3 in 2015. The average Japanese maternal ages were based on the annual nationwide survey data from the Ministry of Health, Labor, and Welfare (http://www.mhlw.go.jp/toukei/list/81-1.html). c Birth OFC SDS ≥ 1.5 above birth length or weight SDS. d BMI ≤ −2 SDS at 2 years. View Large Figure 1. View largeDownload slide (A) Growth charts of patients 1 to 5. (B) Photographs of patients 2 and 5. Both patients presented with frontal bossing. Figure 1. View largeDownload slide (A) Growth charts of patients 1 to 5. (B) Photographs of patients 2 and 5. Both patients presented with frontal bossing. Hormonal findings Table 2 summarizes the hormonal characteristics of patients 1 to 5. Patients 4 and 5 exhibited hypercalcemia, together with low or low-normal intact PTH levels (Fig. 2A). All patients showed high-normal, free triiodothyronine (T3). The serum TSH levels of patient 1 was within the normal range at 5.2 years of age, mildly decreased between 8 and 12 years of age, and remained constantly low after 12.5 years of age, despite normal levels of free T3 and free thyroxine (T4; Fig. 2B). GH provocation tests in patients 1 and 5 suggested normal or high-normal GH secretion, whereas basal IGF-1 was markedly low in three of five patients, including patient 1, and the basal IGF-binding protein 3 level of patient 2 was low. In all patients, gonadotropin and sex hormone levels were within the normal range for prepubertal children. Patient 1 was treated with low-dose estrogen from 13.6 years of age because of the lack of spontaneous pubertal development. Table 2. Hormonal Findings of Our Patients Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Sex  Female  Male  Female  Female  Male  Age at examination, y:mo  15:1  10:9  07:10  2:2  2:4   Calcium, mM  2.37 (2.17–2.55)  2.40 (2.17–2.55)  2.47 (2.17–2.55)  2.71 (2.20–2.65)  2.69 (2.20–2.65)   Inorganic phosphate, mM  1.23 (0.90–1.86)  1.84 (1.22–1.99)  1.58 (1.22–1.99)  1.48 (1.22–1.99)  1.55 (1.22–1.99)   Alkaline phosphatase, IU/L  954 (300–975)  950 (300–975)  631 (300–975)  795 (300–975)  661 (300–975)   Intact PTH, pM  3.7 (1.5–8.3)  4.3 (1.5–8.3)  1.8 (1.5–8.3)  1.1 (1.5–8.3)  1.7 (1.5–8.3)   1,25 (OH)2 vitamin D, pM  157 (48–167)  145 (48–167)  62 (48–167)  156 (48–167)  79 (48–167)   TSH, mIU/L  <0.02 (0.4–4.0)  1.02 (0.4–4.0)  1.25 (0.4–4.0)  2.37 (0.4–4.0)  2.27 (0.4–4.0)   Free T3, pM  5.8 (3.5–6.7)  7.4 (3.9–7.4)  6.2 (3.8–7.0)  6.6 (3.5–6.7)  6.0 (3.5–6.7)   Free T4, pM  17.5 (12.2–23.6)  14.7 (13.0–25.2)  17.1 (13.4–25.9)  14.2 (12.9–24.8)  14.3 (12.9–24.8)   LH, IU/L  2.7 (0.4–6.5)  0.5 (<4.3)  <0.1 (<0.3)  <0.2 (<0.3)  <0.1 (<0.3)   FSH, IU/L  3.4 (0.3–7.8)  1.2 (0.4–3.9)  1.4 (0.4–5.5)  3 (0.4–5.5)  0.6 (<0.9)   Estradiol, pM  51.4 (<936)  NE  <18.4 (<37)  NE  NE   Testosterone, nM  NE  0.8(0.1–2.4)  NE  NE  0.1 (0.1–1.1)   GH (basal/peak), μg/L  0.73/70.7a  NE  NE  NE  2.4/14.6b  Age at examination, y:mo  09:01  01:00  05:07  01:08  02:00   IGFBP3, μg/mL  NE  1.02 (1.02–2.05)  NE  NE  NE   IGF-1, ng/mL  91 (133–517)  12 (14–148)  107 (89–357)  19 (32–186)  20 (18–154)  Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Sex  Female  Male  Female  Female  Male  Age at examination, y:mo  15:1  10:9  07:10  2:2  2:4   Calcium, mM  2.37 (2.17–2.55)  2.40 (2.17–2.55)  2.47 (2.17–2.55)  2.71 (2.20–2.65)  2.69 (2.20–2.65)   Inorganic phosphate, mM  1.23 (0.90–1.86)  1.84 (1.22–1.99)  1.58 (1.22–1.99)  1.48 (1.22–1.99)  1.55 (1.22–1.99)   Alkaline phosphatase, IU/L  954 (300–975)  950 (300–975)  631 (300–975)  795 (300–975)  661 (300–975)   Intact PTH, pM  3.7 (1.5–8.3)  4.3 (1.5–8.3)  1.8 (1.5–8.3)  1.1 (1.5–8.3)  1.7 (1.5–8.3)   1,25 (OH)2 vitamin D, pM  157 (48–167)  145 (48–167)  62 (48–167)  156 (48–167)  79 (48–167)   TSH, mIU/L  <0.02 (0.4–4.0)  1.02 (0.4–4.0)  1.25 (0.4–4.0)  2.37 (0.4–4.0)  2.27 (0.4–4.0)   Free T3, pM  5.8 (3.5–6.7)  7.4 (3.9–7.4)  6.2 (3.8–7.0)  6.6 (3.5–6.7)  6.0 (3.5–6.7)   Free T4, pM  17.5 (12.2–23.6)  14.7 (13.0–25.2)  17.1 (13.4–25.9)  14.2 (12.9–24.8)  14.3 (12.9–24.8)   LH, IU/L  2.7 (0.4–6.5)  0.5 (<4.3)  <0.1 (<0.3)  <0.2 (<0.3)  <0.1 (<0.3)   FSH, IU/L  3.4 (0.3–7.8)  1.2 (0.4–3.9)  1.4 (0.4–5.5)  3 (0.4–5.5)  0.6 (<0.9)   Estradiol, pM  51.4 (<936)  NE  <18.4 (<37)  NE  NE   Testosterone, nM  NE  0.8(0.1–2.4)  NE  NE  0.1 (0.1–1.1)   GH (basal/peak), μg/L  0.73/70.7a  NE  NE  NE  2.4/14.6b  Age at examination, y:mo  09:01  01:00  05:07  01:08  02:00   IGFBP3, μg/mL  NE  1.02 (1.02–2.05)  NE  NE  NE   IGF-1, ng/mL  91 (133–517)  12 (14–148)  107 (89–357)  19 (32–186)  20 (18–154)  The hormone values above and below the age- and sex-matched reference ranges are in boldface. The numbers, in parentheses, of hormone values indicate reference ranges. Abbreviations: IGFBP3, IGF-binding protein 3. a GH-releasing peptide 2 stimulation at 9 years and 1 month of age. Peak GH responses to GH-releasing peptide 2 in non-GH-deficient short children was 54.4 ± 2.7 ng/mL [Pihoker et al. (5)]. b Arginine stimulation at 2 years of age. View Large Table 2. Hormonal Findings of Our Patients Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Sex  Female  Male  Female  Female  Male  Age at examination, y:mo  15:1  10:9  07:10  2:2  2:4   Calcium, mM  2.37 (2.17–2.55)  2.40 (2.17–2.55)  2.47 (2.17–2.55)  2.71 (2.20–2.65)  2.69 (2.20–2.65)   Inorganic phosphate, mM  1.23 (0.90–1.86)  1.84 (1.22–1.99)  1.58 (1.22–1.99)  1.48 (1.22–1.99)  1.55 (1.22–1.99)   Alkaline phosphatase, IU/L  954 (300–975)  950 (300–975)  631 (300–975)  795 (300–975)  661 (300–975)   Intact PTH, pM  3.7 (1.5–8.3)  4.3 (1.5–8.3)  1.8 (1.5–8.3)  1.1 (1.5–8.3)  1.7 (1.5–8.3)   1,25 (OH)2 vitamin D, pM  157 (48–167)  145 (48–167)  62 (48–167)  156 (48–167)  79 (48–167)   TSH, mIU/L  <0.02 (0.4–4.0)  1.02 (0.4–4.0)  1.25 (0.4–4.0)  2.37 (0.4–4.0)  2.27 (0.4–4.0)   Free T3, pM  5.8 (3.5–6.7)  7.4 (3.9–7.4)  6.2 (3.8–7.0)  6.6 (3.5–6.7)  6.0 (3.5–6.7)   Free T4, pM  17.5 (12.2–23.6)  14.7 (13.0–25.2)  17.1 (13.4–25.9)  14.2 (12.9–24.8)  14.3 (12.9–24.8)   LH, IU/L  2.7 (0.4–6.5)  0.5 (<4.3)  <0.1 (<0.3)  <0.2 (<0.3)  <0.1 (<0.3)   FSH, IU/L  3.4 (0.3–7.8)  1.2 (0.4–3.9)  1.4 (0.4–5.5)  3 (0.4–5.5)  0.6 (<0.9)   Estradiol, pM  51.4 (<936)  NE  <18.4 (<37)  NE  NE   Testosterone, nM  NE  0.8(0.1–2.4)  NE  NE  0.1 (0.1–1.1)   GH (basal/peak), μg/L  0.73/70.7a  NE  NE  NE  2.4/14.6b  Age at examination, y:mo  09:01  01:00  05:07  01:08  02:00   IGFBP3, μg/mL  NE  1.02 (1.02–2.05)  NE  NE  NE   IGF-1, ng/mL  91 (133–517)  12 (14–148)  107 (89–357)  19 (32–186)  20 (18–154)  Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Sex  Female  Male  Female  Female  Male  Age at examination, y:mo  15:1  10:9  07:10  2:2  2:4   Calcium, mM  2.37 (2.17–2.55)  2.40 (2.17–2.55)  2.47 (2.17–2.55)  2.71 (2.20–2.65)  2.69 (2.20–2.65)   Inorganic phosphate, mM  1.23 (0.90–1.86)  1.84 (1.22–1.99)  1.58 (1.22–1.99)  1.48 (1.22–1.99)  1.55 (1.22–1.99)   Alkaline phosphatase, IU/L  954 (300–975)  950 (300–975)  631 (300–975)  795 (300–975)  661 (300–975)   Intact PTH, pM  3.7 (1.5–8.3)  4.3 (1.5–8.3)  1.8 (1.5–8.3)  1.1 (1.5–8.3)  1.7 (1.5–8.3)   1,25 (OH)2 vitamin D, pM  157 (48–167)  145 (48–167)  62 (48–167)  156 (48–167)  79 (48–167)   TSH, mIU/L  <0.02 (0.4–4.0)  1.02 (0.4–4.0)  1.25 (0.4–4.0)  2.37 (0.4–4.0)  2.27 (0.4–4.0)   Free T3, pM  5.8 (3.5–6.7)  7.4 (3.9–7.4)  6.2 (3.8–7.0)  6.6 (3.5–6.7)  6.0 (3.5–6.7)   Free T4, pM  17.5 (12.2–23.6)  14.7 (13.0–25.2)  17.1 (13.4–25.9)  14.2 (12.9–24.8)  14.3 (12.9–24.8)   LH, IU/L  2.7 (0.4–6.5)  0.5 (<4.3)  <0.1 (<0.3)  <0.2 (<0.3)  <0.1 (<0.3)   FSH, IU/L  3.4 (0.3–7.8)  1.2 (0.4–3.9)  1.4 (0.4–5.5)  3 (0.4–5.5)  0.6 (<0.9)   Estradiol, pM  51.4 (<936)  NE  <18.4 (<37)  NE  NE   Testosterone, nM  NE  0.8(0.1–2.4)  NE  NE  0.1 (0.1–1.1)   GH (basal/peak), μg/L  0.73/70.7a  NE  NE  NE  2.4/14.6b  Age at examination, y:mo  09:01  01:00  05:07  01:08  02:00   IGFBP3, μg/mL  NE  1.02 (1.02–2.05)  NE  NE  NE   IGF-1, ng/mL  91 (133–517)  12 (14–148)  107 (89–357)  19 (32–186)  20 (18–154)  The hormone values above and below the age- and sex-matched reference ranges are in boldface. The numbers, in parentheses, of hormone values indicate reference ranges. Abbreviations: IGFBP3, IGF-binding protein 3. a GH-releasing peptide 2 stimulation at 9 years and 1 month of age. Peak GH responses to GH-releasing peptide 2 in non-GH-deficient short children was 54.4 ± 2.7 ng/mL [Pihoker et al. (5)]. b Arginine stimulation at 2 years of age. View Large Figure 2. View largeDownload slide (A) Calcium and intact PTH levels in patients 4 and 5. The hormone levels above and below the age- and sex-matched reference ranges are in boldface. NE, not examined. (B) TSH and T3 levels of patient 1. Normal TSH levels: 0.4 to 4.0 mIU/L. Solid line indicates lower limit of the reference TSH levels. The upper and lower limits of the age-matched reference ranges of free T3 are shown by the black broken line and the gray broken line, respectively. m, month; y, year. Figure 2. View largeDownload slide (A) Calcium and intact PTH levels in patients 4 and 5. The hormone levels above and below the age- and sex-matched reference ranges are in boldface. NE, not examined. (B) TSH and T3 levels of patient 1. Normal TSH levels: 0.4 to 4.0 mIU/L. Solid line indicates lower limit of the reference TSH levels. The upper and lower limits of the age-matched reference ranges of free T3 are shown by the black broken line and the gray broken line, respectively. m, month; y, year. Discussion Here, we report five patients with nonmosaic UPD(20)mat. Patients 1 to 5 invariably manifested postnatal growth failure with feeding difficulties and/or low BMI. In addition, most patients showed hypoplastic placenta, oligohydramnios, and delayed bone age. Such clinical features were also documented in previously reported UPD(20)mat cases (3). This phenotype is attributable to deficiency of paternally expressed GNAS transcripts, including XLαs and A/B (6), as mice lacking XLαs on the paternal allele showed poor sucking and postnatal growth failure (7, 8), and animals lacking paternal exon 1A (corresponding to human A/B) exhibited prenatal growth retardation (9). Relative macrocephaly at birth and present appears to be less important in UPD(20)mat than in patients with SRS. Developmental delay of patients 4 and 5 may reflect hypotonia. This may be a transient feature, as four previously reported UPD(20)mat cases exhibited hypotonia in infancy but demonstrated normal development thereafter (3). The association between hypotonia and abnormal expression of GNAS transcripts remains to be clarified. On the other hand, intellectual disability in patient 1 with isodisomy may have been caused by an unmasked autosomal recessive mutation(s). In this study, UPD(20)mat accounted for 5.5% (three of 55) of patients with etiology-unknown SRS and 1.0% (one of 96) of patients with SGA-SS. Patients 1 to 3 met the diagnostic criteria of the Netchine-Harbison clinical scoring system (4), which is currently the most reliable scoring system for SRS, and the remaining two patients exhibited several SRS-compatible features. Moreover, four of five patients were born SGA. These results highlight the clinical significance of UPD(20)mat as a genetic cause of SRS and SGA-SS. In addition, the results for patient 5 indicate that UPD(20)mat can also underlie SS without SGA. Three of four patients with heterodisomy were born to mothers with advanced ages (Table 1). As advanced maternal age increases the risk of aneuploidy in oocyte, and maternal heterodisomy arises from disomic oocyte (Supplemental Fig. 2), advanced maternal age may increase the risk of UPD(20)mat. The most remarkable finding of this study was the endocrinological abnormalities of UPD(20)mat. Hypercalcemia with low or low-normal intact PTH in patients 4 and 5 can be explained by increased sensitivity of the PTH receptor as a result of Gsα overexpression. Likewise, high-normal, free T3 in all patients and low TSH in patient 1 may reflect TSH receptor hypersensitivity. In fact, McCune-Albright syndrome caused by somatic-activating GNAS mutations also manifests as hyperthyroidism (1). As blood TSH levels of patient 1 progressively decreased after 8 years of age, the hormone hypersensitivity associated with UPD(20)mat may gradually develop with age. However, one may argue against UPD(20)mat being responsible for the hormonal abnormalities observed in patients 1 to 5, as blood levels of GH, gonadotropins, and sex hormones were within the normal range, despite the fact that Gsα mediates the signal transduction of the receptor of GH-releasing hormone, LH, and FSH (1). Nevertheless, our results are consistent with previous findings that the imprinting status of the GNAS locus is less strictly regulated in the pituitary and ovary than in the proximal renal tubule and thyroid, and even in the thyroid, the imprinting status varied in individuals (10). Whereas low IGF-1 levels were observed in most of our patients and previously reported cases, this may reflect poor nutrition rather than GH deficiency. Indeed, GH provocative tests in patients 1 and 5 suggested normal GH secretion. As suboptimal GH secretion has been reported in four pseudohypoparathyroidism type 1b patients (11), further studies are necessary to clarify the hormonal characteristics of patients with UPD(20)mat. In summary, the results suggest that UPD(20)mat underlies severe growth failure and feeding difficulties and may account for >5% of cases of SRS of unknown etiology and small percentages of SGA-SS and non-SGA-SS. Most importantly, this study provides an indication that UPD(20)mat is associated with hypersensitivity of Gsα-mediated hormone receptors, which may gradually develop with age. Abbreviations: Abbreviations: BMI body mass index FSH follicle-stimulating hormone GH growth hormone GNAS guanine nucleotide binding protein, alpha stimulating Gsα α-subunit of the stimulatory G protein IGF-1 insulinlike growth factor 1 LH luteinizing hormone OFC occipitofrontal circumference PTH parathyroid hormone SDS standard deviation score SGA-SS small for gestational age-short stature SRS Silver-Russell syndrome T3 triiodothyronine T4 thyroxine TSH thyroid-stimulating hormone UPD(20)mat maternal uniparental disomy for chromosome 20 XLαs extra large form of Gsα Acknowledgments We thank the patients and their family members for their cooperation. We also thank Ms. Shigeko Honjyo for her support in collecting clinical information. Financial Support: This work was supported by grants from the Japan Society for the Promotion of Science (JSPS; 15K15096 and 17H06428), National Center for Child Health and Development (28-6), Japan Agency for Medical Research and Development (AMED; 17ek0109278h0001, 16ek0109030h0003, and 16ek0109141h0002), the Takeda Science Foundation, and Japanese Society for Pediatric Endocrinology Future Development Grant. Disclosure Summary: The authors have nothing to disclose. References 1. Turan S, Bastepe M. GNAS spectrum of disorders. Curr Osteoporos Rep . 2015; 13( 3): 146– 158. Google Scholar CrossRef Search ADS PubMed  2. Takatani R, Minagawa M, Molinaro A, Reyes M, Kinoshita K, Takatani T, Kazukawa I, Nagatsuma M, Kashimada K, Sato K, Matsushita K, Nomura F, Shimojo N, Jüppner H. Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B). Bone . 2015; 79: 15– 20. Google Scholar CrossRef Search ADS PubMed  3. Mulchandani S, Bhoj EJ, Luo M, Powell-Hamilton N, Jenny K, Gripp KW, Elbracht M, Eggermann T, Turner CL, Temple IK, Mackay DJ, Dubbs H, Stevenson DA, Slattery L, Zackai EH, Spinner NB, Krantz ID, Conlin LK. Maternal uniparental disomy of chromosome 20: a novel imprinting disorder of growth failure. Genet Med . 2016; 18( 4): 309– 315. Google Scholar CrossRef Search ADS PubMed  4. Azzi S, Salem J, Thibaud N, Chantot-Bastaraud S, Lieber E, Netchine I, Harbison MD. A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome. J Med Genet . 2015; 52( 7): 446– 453. Google Scholar CrossRef Search ADS PubMed  5. Pihoker C, Middleton R, Reynolds GA, Bowers CY, Badger TM. Diagnostic studies with intravenous and intranasal GHRP-2 in children of short stature. J Clin Endocrinol Metab . 1995; 80( 10): 2987– 2992. Google Scholar PubMed  6. Geneviève D, Sanlaville D, Faivre L, Kottler ML, Jambou M, Gosset P, Boustani-Samara D, Pinto G, Ozilou C, Abeguilé G, Munnich A, Romana S, Raoul O, Cormier-Daire V, Vekemans M. Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties. Eur J Hum Genet . 2005; 13( 9): 1033– 1039. Google Scholar CrossRef Search ADS PubMed  7. Plagge A, Gordon E, Dean W, Boiani R, Cinti S, Peters J, Kelsey G. The imprinted signaling protein XL α s is required for postnatal adaptation to feeding. Nat Genet . 2004; 36( 8): 818– 826. Google Scholar CrossRef Search ADS PubMed  8. Xie T, Plagge A, Gavrilova O, Pack S, Jou W, Lai EW, Frontera M, Kelsey G, Weinstein LS. The alternative stimulatory G protein α-subunit XLalphas is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice. J Biol Chem . 2006; 281( 28): 18989– 18999. Google Scholar CrossRef Search ADS PubMed  9. Ball ST, Kelly ML, Robson JE, Turner MD, Harrison J, Jones L, Napper D, Beechey CV, Hough T, Plagge A, Cattanach BM, Cox RD, Peters J. Gene dosage effects at the imprinted Gnas cluster. PLoS One . 2013; 8( 6): e65639. Google Scholar CrossRef Search ADS PubMed  10. Mantovani G, Ballare E, Giammona E, Beck-Peccoz P, Spada A. The gsalpha gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab . 2002; 87( 10): 4736– 4740. Google Scholar CrossRef Search ADS PubMed  11. Sano S, Iwata H, Matsubara K, Fukami M, Kagami M, Ogata T. Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib. Endocr J . 2015; 62( 6): 523– 529. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

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Endocrine Society
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Copyright © 2018 Endocrine Society
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0021-972X
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1945-7197
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10.1210/jc.2017-02780
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Abstract

Abstract Context Maternal uniparental disomy for chromosome 20 [UPD(20)mat], resulting in aberrant expression of imprinted transcripts at the GNAS locus, is a poorly characterized condition. These patients manifested a phenotype similar to that of Silver-Russell syndrome (SRS) and small for gestational age-short stature (SGA-SS); however, the etiological relationship between UPD(20)mat and SRS/SGA-SS remains unclear. Moreover, no report has described endocrinological assessment of UPD(20)mat patients, although paternal UPD(20), the mirror image entity of UPD(20)mat, is known to cause multiple hormone resistance reflecting reduced α-subunit of the stimulatory G protein expression. Participants Patients 1 to 5 showed nonmosaic heterodisomy and/or isodisomy for the entire chromosome 20. Patients 1 to 3 and 4 were identified through UPD(20)mat screening for 55 patients with etiology-unknown SRS and 96 patients with SGA-SS, respectively. Patient 5 was identified through molecular analysis for patients with developmental defects. Patients 1 to 5 manifested postnatal growth failure and feeding problems, with or without developmental delay, and other clinical features. Patients 1 to 4 were born SGA. Patients 4 and 5 exhibited hypercalcemia and low or low-normal parathyroid hormone levels. Patient 1 showed constantly decreased thyroid-stimulating hormone (TSH) levels after 12 years of age, although she had a normal TSH level at 5.2 years of age. Conclusion The results suggest that UPD(20)mat underlies growth failure and feeding problems with additional features and could account for >5% of etiology-unknown SRS and small percentages of SGA-SS. Most important, this study provides an indication that UPD(20)mat can be associated with hypersensitivity of hormone receptors, which may gradually develop with age. The guanine nucleotide binding protein, alpha stimulating (GNAS) locus on 20q13 encompasses several imprinted transcripts, including α-subunit of the stimulatory G protein (Gsα), extra large form of Gsα (XLαs), and A/B (1). Of these, Gsα is expressed in the proximal renal tubule, thyroid, pituitary, and ovary, predominantly from the maternally derived allele (1), whereas XLαs and A/B are expressed in various tissues primarily from the paternally derived allele (1). Gsα regulates the cyclic adenosine monophosphate-mediated signaling cascade of the receptors of parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), growth hormone (GH)-releasing hormone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) (1). Consequently, paternal uniparental disomy for chromosome 20 causes multiple hormone resistance, reflecting reduced Gsα expression (2). Paternal uniparental disomy for chromosome 20 typically results in pseudohypoparathyroidism and hypothyroidism and accounts for ∼10% of patients with sporadic pseudohypoparathyroidism type 1b (2). In contrast, maternal uniparental disomy for chromosome 20 [UPD(20)mat], particularly UPD(20)mat without trisomy mosaicism, is a poorly characterized condition; only 10 nonmosaic cases have been studied clinically (3, 4). These patients presented with pre- and postnatal growth failure and feeding difficulties. Although the phenotypes of these cases overlapped with that of Silver-Russell syndrome (SRS) and small for gestational age-short stature (SGA-SS) (3, 4), the etiological relationship between UPD(20)mat and SRS/SGA-SS remains uncertain. Moreover, there has been no report of endocrinological assessment of UPD(20)mat patients, except for measurements of basal GH and insulinlike growth factor 1 (IGF-1) levels in some patients. Case Reports Patients 1 to 5 were unrelated Japanese children with nonmosaic UPD(20)mat. Patients 1 to 3 and 4 were identified through DNA methylation analyses for the GNAS locus in 55 patients with SRS of unknown etiology and in 96 patients with SGA-SS, respectively (Supplemental Methods). Patient 5 was identified through molecular analysis for patients with developmental delay and severe growth failure. Comparative genomic hybridization + single nucleotide polymorphism microarray and microsatellite analyses revealed that patients 1 to 5 had maternal UPD for the entire chromosome 20 (Supplemental Fig. 1 and Supplemental Table 1). Patient 1 had full isodisomy, whereas the other patients exhibited isodisomy and heterodisomy. Physical examination findings Patients 1 to 5 exhibited postnatal growth failure, and patients 1 to 4 were born SGA (Table 1, Fig. 1, and Supplemental Table 2). The birth weight, length, and occipitofrontal circumferences (OFCs) of UPD(20)mat patients were larger than those of the other participants with SRS or SGA-SS. The standard deviation scores (SDSs) of the present OFCs were similar to those of the birth OFCs in most UPD(20)mat patients. The SDSs of the present OFCs of UPD(20)mat were significantly larger than those of other participants with SGA-SS. Bone age was delayed in all school-aged patients. GH treatment yielded a good response in patient 2 but not in patient 1 (Fig. 1). Hypoplastic placenta and oligohydramnios were detected in most patients. All of the patients showed feeding difficulties and/or low body mass index (BMI) at 2 years of age. Patients 1 and 3 required gastrostomy or tube feeding for >2 years after birth. Patients 1 to 3 satisfied the diagnostic criteria of the Netchine-Harbison clinical scoring system for SRS (4). Triangular face was present in four patients (Table 1 and Fig. 1). Developmental delay, with or without hypotonia, was observed in three patients. One of three school-aged patients attended a special educational program, whereas the others showed normal achievement in elementary schools. Table 1. Clinical Manifestations of Our Patients and Previously Reported Cases Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Previous Reportsa  Uniparental Disomy Type  Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy    Sex  Female  Male  Female  Female  Male  Male:Female = 5:4  Age at last evaluation, y:mo  15:1  10:9  07:10  2:2  2:4  6 (0:3 ∼ 12)  Pregnancy and delivery               Gestational age, wk  36  34  37  37  36  38 (36 ∼ 39)   Placental weight  235 g  Small  NA  NA  Small     Oligohydramnios  +  +  +  +  −     Paternal age at childbirth, y  35  28  37  39  42     Maternal age at childbirth, yb  33  28  42  41  39  38 (30 ∼ 43)  Growth               Birth length, cm (SDS)  39.0 (–2.7)  40.3 (–1.6)  44.4 (–1.4)  42.6 (–2.3)  47.0 (0.2)     Birth weight, g (SDS)  1252 (–4.1)  1354 (–2.8)  2000 (–1.9)  1935 (–2.2)  2110 (–1.5)  Second percentile (<second ∼ <fifth)   Birth OFC, cm (SDS)  29.5 (–1.7)  29.0 (–1.1)  30.0 (–1.9)  31.2 (–1.2)  30.5 (–1.2)     Present height, cm (SDS)  138.4 (–3.5)  141.6 (0.2)  111.0 (–2.4)  75.3 (–3.5)  77.2 (–3.5)  Fifth percentile (<second ∼ 10th)   Present weight, kg (SDS)  26.4 (–3.0)  26.8 (–1.1)  14.1 (–2.3)  6.7 (–3.9)  8.1 (–3.2)  Fifth percentile (<second ∼ 75th)   Present BMI (SDS)  13.78 (–3.9)  13.37 (–2.7)  11.44 (–3.8)  11.85 (–3.4)  13.59 (–2.0)     Present OFC, cm (SDS)  53.1 (–1.5)  50.7 (–1.8)  49 (–2.0)  45.4 (–1.3)  50.0 (0.7)     Tanner stage at present  Breast 3, Pubic hair 1  NA  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1     GH treatment  +  +  −  −  −  4/9  Development               Hypotonia  −  −  −  +  +     IQ/DQ  IQ 78  DQ 113  NE  DQ 65  DQ 75    Other findings               Feeding difficulties  +  −  +  +  +     Tube feeding or gastrostoma  Gastrostoma (∼10 y)  −  −  Tube feeding (ongoing)  −  6/9   Triangular face  +  −  +  +  +     Abnormalities in the bone structures of the hands and wrists  −  −  −  −  −     Extra features  GER, dermal sinus      Face asymmetry, right low-set ear, scoliosis      Netchine-Harbison scoring system features for SRS               Birth length and/or weight ≤ −2 SDS  +  +  −  +  −     Relative macrocephaly at birthc  +  +  −  −  −     Postnatal height (at 2 y) ≤ −2 SDS  +  +  +  +  +     Prominent forehead (1–3 years)  −  +  +  −  +     Body asymmetry  −  −  +  −  −     Feeding difficulties and/or low BMId  +  +  +  +  +    Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Previous Reportsa  Uniparental Disomy Type  Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy    Sex  Female  Male  Female  Female  Male  Male:Female = 5:4  Age at last evaluation, y:mo  15:1  10:9  07:10  2:2  2:4  6 (0:3 ∼ 12)  Pregnancy and delivery               Gestational age, wk  36  34  37  37  36  38 (36 ∼ 39)   Placental weight  235 g  Small  NA  NA  Small     Oligohydramnios  +  +  +  +  −     Paternal age at childbirth, y  35  28  37  39  42     Maternal age at childbirth, yb  33  28  42  41  39  38 (30 ∼ 43)  Growth               Birth length, cm (SDS)  39.0 (–2.7)  40.3 (–1.6)  44.4 (–1.4)  42.6 (–2.3)  47.0 (0.2)     Birth weight, g (SDS)  1252 (–4.1)  1354 (–2.8)  2000 (–1.9)  1935 (–2.2)  2110 (–1.5)  Second percentile (<second ∼ <fifth)   Birth OFC, cm (SDS)  29.5 (–1.7)  29.0 (–1.1)  30.0 (–1.9)  31.2 (–1.2)  30.5 (–1.2)     Present height, cm (SDS)  138.4 (–3.5)  141.6 (0.2)  111.0 (–2.4)  75.3 (–3.5)  77.2 (–3.5)  Fifth percentile (<second ∼ 10th)   Present weight, kg (SDS)  26.4 (–3.0)  26.8 (–1.1)  14.1 (–2.3)  6.7 (–3.9)  8.1 (–3.2)  Fifth percentile (<second ∼ 75th)   Present BMI (SDS)  13.78 (–3.9)  13.37 (–2.7)  11.44 (–3.8)  11.85 (–3.4)  13.59 (–2.0)     Present OFC, cm (SDS)  53.1 (–1.5)  50.7 (–1.8)  49 (–2.0)  45.4 (–1.3)  50.0 (0.7)     Tanner stage at present  Breast 3, Pubic hair 1  NA  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1     GH treatment  +  +  −  −  −  4/9  Development               Hypotonia  −  −  −  +  +     IQ/DQ  IQ 78  DQ 113  NE  DQ 65  DQ 75    Other findings               Feeding difficulties  +  −  +  +  +     Tube feeding or gastrostoma  Gastrostoma (∼10 y)  −  −  Tube feeding (ongoing)  −  6/9   Triangular face  +  −  +  +  +     Abnormalities in the bone structures of the hands and wrists  −  −  −  −  −     Extra features  GER, dermal sinus      Face asymmetry, right low-set ear, scoliosis      Netchine-Harbison scoring system features for SRS               Birth length and/or weight ≤ −2 SDS  +  +  −  +  −     Relative macrocephaly at birthc  +  +  −  −  −     Postnatal height (at 2 y) ≤ −2 SDS  +  +  +  +  +     Prominent forehead (1–3 years)  −  +  +  −  +     Body asymmetry  −  −  +  −  −     Feeding difficulties and/or low BMId  +  +  +  +  +    Abbreviations: GER, gastroesophageal reflex; IQ/DQ, intellectual/developmental quotient; NA, not available; NE, not examined; a See Mulchandani et al. (3). b Patients 1 to 5 were born in 2002, 2006, 2009, 2015, and 2015, respectively. The average Japanese maternal ages were 29.8 years of age in 2002, 30.5 in 2006, 31.0 in 2009, and 31.3 in 2015. The average Japanese maternal ages were based on the annual nationwide survey data from the Ministry of Health, Labor, and Welfare (http://www.mhlw.go.jp/toukei/list/81-1.html). c Birth OFC SDS ≥ 1.5 above birth length or weight SDS. d BMI ≤ −2 SDS at 2 years. View Large Table 1. Clinical Manifestations of Our Patients and Previously Reported Cases Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Previous Reportsa  Uniparental Disomy Type  Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy    Sex  Female  Male  Female  Female  Male  Male:Female = 5:4  Age at last evaluation, y:mo  15:1  10:9  07:10  2:2  2:4  6 (0:3 ∼ 12)  Pregnancy and delivery               Gestational age, wk  36  34  37  37  36  38 (36 ∼ 39)   Placental weight  235 g  Small  NA  NA  Small     Oligohydramnios  +  +  +  +  −     Paternal age at childbirth, y  35  28  37  39  42     Maternal age at childbirth, yb  33  28  42  41  39  38 (30 ∼ 43)  Growth               Birth length, cm (SDS)  39.0 (–2.7)  40.3 (–1.6)  44.4 (–1.4)  42.6 (–2.3)  47.0 (0.2)     Birth weight, g (SDS)  1252 (–4.1)  1354 (–2.8)  2000 (–1.9)  1935 (–2.2)  2110 (–1.5)  Second percentile (<second ∼ <fifth)   Birth OFC, cm (SDS)  29.5 (–1.7)  29.0 (–1.1)  30.0 (–1.9)  31.2 (–1.2)  30.5 (–1.2)     Present height, cm (SDS)  138.4 (–3.5)  141.6 (0.2)  111.0 (–2.4)  75.3 (–3.5)  77.2 (–3.5)  Fifth percentile (<second ∼ 10th)   Present weight, kg (SDS)  26.4 (–3.0)  26.8 (–1.1)  14.1 (–2.3)  6.7 (–3.9)  8.1 (–3.2)  Fifth percentile (<second ∼ 75th)   Present BMI (SDS)  13.78 (–3.9)  13.37 (–2.7)  11.44 (–3.8)  11.85 (–3.4)  13.59 (–2.0)     Present OFC, cm (SDS)  53.1 (–1.5)  50.7 (–1.8)  49 (–2.0)  45.4 (–1.3)  50.0 (0.7)     Tanner stage at present  Breast 3, Pubic hair 1  NA  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1     GH treatment  +  +  −  −  −  4/9  Development               Hypotonia  −  −  −  +  +     IQ/DQ  IQ 78  DQ 113  NE  DQ 65  DQ 75    Other findings               Feeding difficulties  +  −  +  +  +     Tube feeding or gastrostoma  Gastrostoma (∼10 y)  −  −  Tube feeding (ongoing)  −  6/9   Triangular face  +  −  +  +  +     Abnormalities in the bone structures of the hands and wrists  −  −  −  −  −     Extra features  GER, dermal sinus      Face asymmetry, right low-set ear, scoliosis      Netchine-Harbison scoring system features for SRS               Birth length and/or weight ≤ −2 SDS  +  +  −  +  −     Relative macrocephaly at birthc  +  +  −  −  −     Postnatal height (at 2 y) ≤ −2 SDS  +  +  +  +  +     Prominent forehead (1–3 years)  −  +  +  −  +     Body asymmetry  −  −  +  −  −     Feeding difficulties and/or low BMId  +  +  +  +  +    Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Previous Reportsa  Uniparental Disomy Type  Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy  Heterodisomy and Isodisomy    Sex  Female  Male  Female  Female  Male  Male:Female = 5:4  Age at last evaluation, y:mo  15:1  10:9  07:10  2:2  2:4  6 (0:3 ∼ 12)  Pregnancy and delivery               Gestational age, wk  36  34  37  37  36  38 (36 ∼ 39)   Placental weight  235 g  Small  NA  NA  Small     Oligohydramnios  +  +  +  +  −     Paternal age at childbirth, y  35  28  37  39  42     Maternal age at childbirth, yb  33  28  42  41  39  38 (30 ∼ 43)  Growth               Birth length, cm (SDS)  39.0 (–2.7)  40.3 (–1.6)  44.4 (–1.4)  42.6 (–2.3)  47.0 (0.2)     Birth weight, g (SDS)  1252 (–4.1)  1354 (–2.8)  2000 (–1.9)  1935 (–2.2)  2110 (–1.5)  Second percentile (<second ∼ <fifth)   Birth OFC, cm (SDS)  29.5 (–1.7)  29.0 (–1.1)  30.0 (–1.9)  31.2 (–1.2)  30.5 (–1.2)     Present height, cm (SDS)  138.4 (–3.5)  141.6 (0.2)  111.0 (–2.4)  75.3 (–3.5)  77.2 (–3.5)  Fifth percentile (<second ∼ 10th)   Present weight, kg (SDS)  26.4 (–3.0)  26.8 (–1.1)  14.1 (–2.3)  6.7 (–3.9)  8.1 (–3.2)  Fifth percentile (<second ∼ 75th)   Present BMI (SDS)  13.78 (–3.9)  13.37 (–2.7)  11.44 (–3.8)  11.85 (–3.4)  13.59 (–2.0)     Present OFC, cm (SDS)  53.1 (–1.5)  50.7 (–1.8)  49 (–2.0)  45.4 (–1.3)  50.0 (0.7)     Tanner stage at present  Breast 3, Pubic hair 1  NA  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1  Breast 1, Pubic hair 1     GH treatment  +  +  −  −  −  4/9  Development               Hypotonia  −  −  −  +  +     IQ/DQ  IQ 78  DQ 113  NE  DQ 65  DQ 75    Other findings               Feeding difficulties  +  −  +  +  +     Tube feeding or gastrostoma  Gastrostoma (∼10 y)  −  −  Tube feeding (ongoing)  −  6/9   Triangular face  +  −  +  +  +     Abnormalities in the bone structures of the hands and wrists  −  −  −  −  −     Extra features  GER, dermal sinus      Face asymmetry, right low-set ear, scoliosis      Netchine-Harbison scoring system features for SRS               Birth length and/or weight ≤ −2 SDS  +  +  −  +  −     Relative macrocephaly at birthc  +  +  −  −  −     Postnatal height (at 2 y) ≤ −2 SDS  +  +  +  +  +     Prominent forehead (1–3 years)  −  +  +  −  +     Body asymmetry  −  −  +  −  −     Feeding difficulties and/or low BMId  +  +  +  +  +    Abbreviations: GER, gastroesophageal reflex; IQ/DQ, intellectual/developmental quotient; NA, not available; NE, not examined; a See Mulchandani et al. (3). b Patients 1 to 5 were born in 2002, 2006, 2009, 2015, and 2015, respectively. The average Japanese maternal ages were 29.8 years of age in 2002, 30.5 in 2006, 31.0 in 2009, and 31.3 in 2015. The average Japanese maternal ages were based on the annual nationwide survey data from the Ministry of Health, Labor, and Welfare (http://www.mhlw.go.jp/toukei/list/81-1.html). c Birth OFC SDS ≥ 1.5 above birth length or weight SDS. d BMI ≤ −2 SDS at 2 years. View Large Figure 1. View largeDownload slide (A) Growth charts of patients 1 to 5. (B) Photographs of patients 2 and 5. Both patients presented with frontal bossing. Figure 1. View largeDownload slide (A) Growth charts of patients 1 to 5. (B) Photographs of patients 2 and 5. Both patients presented with frontal bossing. Hormonal findings Table 2 summarizes the hormonal characteristics of patients 1 to 5. Patients 4 and 5 exhibited hypercalcemia, together with low or low-normal intact PTH levels (Fig. 2A). All patients showed high-normal, free triiodothyronine (T3). The serum TSH levels of patient 1 was within the normal range at 5.2 years of age, mildly decreased between 8 and 12 years of age, and remained constantly low after 12.5 years of age, despite normal levels of free T3 and free thyroxine (T4; Fig. 2B). GH provocation tests in patients 1 and 5 suggested normal or high-normal GH secretion, whereas basal IGF-1 was markedly low in three of five patients, including patient 1, and the basal IGF-binding protein 3 level of patient 2 was low. In all patients, gonadotropin and sex hormone levels were within the normal range for prepubertal children. Patient 1 was treated with low-dose estrogen from 13.6 years of age because of the lack of spontaneous pubertal development. Table 2. Hormonal Findings of Our Patients Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Sex  Female  Male  Female  Female  Male  Age at examination, y:mo  15:1  10:9  07:10  2:2  2:4   Calcium, mM  2.37 (2.17–2.55)  2.40 (2.17–2.55)  2.47 (2.17–2.55)  2.71 (2.20–2.65)  2.69 (2.20–2.65)   Inorganic phosphate, mM  1.23 (0.90–1.86)  1.84 (1.22–1.99)  1.58 (1.22–1.99)  1.48 (1.22–1.99)  1.55 (1.22–1.99)   Alkaline phosphatase, IU/L  954 (300–975)  950 (300–975)  631 (300–975)  795 (300–975)  661 (300–975)   Intact PTH, pM  3.7 (1.5–8.3)  4.3 (1.5–8.3)  1.8 (1.5–8.3)  1.1 (1.5–8.3)  1.7 (1.5–8.3)   1,25 (OH)2 vitamin D, pM  157 (48–167)  145 (48–167)  62 (48–167)  156 (48–167)  79 (48–167)   TSH, mIU/L  <0.02 (0.4–4.0)  1.02 (0.4–4.0)  1.25 (0.4–4.0)  2.37 (0.4–4.0)  2.27 (0.4–4.0)   Free T3, pM  5.8 (3.5–6.7)  7.4 (3.9–7.4)  6.2 (3.8–7.0)  6.6 (3.5–6.7)  6.0 (3.5–6.7)   Free T4, pM  17.5 (12.2–23.6)  14.7 (13.0–25.2)  17.1 (13.4–25.9)  14.2 (12.9–24.8)  14.3 (12.9–24.8)   LH, IU/L  2.7 (0.4–6.5)  0.5 (<4.3)  <0.1 (<0.3)  <0.2 (<0.3)  <0.1 (<0.3)   FSH, IU/L  3.4 (0.3–7.8)  1.2 (0.4–3.9)  1.4 (0.4–5.5)  3 (0.4–5.5)  0.6 (<0.9)   Estradiol, pM  51.4 (<936)  NE  <18.4 (<37)  NE  NE   Testosterone, nM  NE  0.8(0.1–2.4)  NE  NE  0.1 (0.1–1.1)   GH (basal/peak), μg/L  0.73/70.7a  NE  NE  NE  2.4/14.6b  Age at examination, y:mo  09:01  01:00  05:07  01:08  02:00   IGFBP3, μg/mL  NE  1.02 (1.02–2.05)  NE  NE  NE   IGF-1, ng/mL  91 (133–517)  12 (14–148)  107 (89–357)  19 (32–186)  20 (18–154)  Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Sex  Female  Male  Female  Female  Male  Age at examination, y:mo  15:1  10:9  07:10  2:2  2:4   Calcium, mM  2.37 (2.17–2.55)  2.40 (2.17–2.55)  2.47 (2.17–2.55)  2.71 (2.20–2.65)  2.69 (2.20–2.65)   Inorganic phosphate, mM  1.23 (0.90–1.86)  1.84 (1.22–1.99)  1.58 (1.22–1.99)  1.48 (1.22–1.99)  1.55 (1.22–1.99)   Alkaline phosphatase, IU/L  954 (300–975)  950 (300–975)  631 (300–975)  795 (300–975)  661 (300–975)   Intact PTH, pM  3.7 (1.5–8.3)  4.3 (1.5–8.3)  1.8 (1.5–8.3)  1.1 (1.5–8.3)  1.7 (1.5–8.3)   1,25 (OH)2 vitamin D, pM  157 (48–167)  145 (48–167)  62 (48–167)  156 (48–167)  79 (48–167)   TSH, mIU/L  <0.02 (0.4–4.0)  1.02 (0.4–4.0)  1.25 (0.4–4.0)  2.37 (0.4–4.0)  2.27 (0.4–4.0)   Free T3, pM  5.8 (3.5–6.7)  7.4 (3.9–7.4)  6.2 (3.8–7.0)  6.6 (3.5–6.7)  6.0 (3.5–6.7)   Free T4, pM  17.5 (12.2–23.6)  14.7 (13.0–25.2)  17.1 (13.4–25.9)  14.2 (12.9–24.8)  14.3 (12.9–24.8)   LH, IU/L  2.7 (0.4–6.5)  0.5 (<4.3)  <0.1 (<0.3)  <0.2 (<0.3)  <0.1 (<0.3)   FSH, IU/L  3.4 (0.3–7.8)  1.2 (0.4–3.9)  1.4 (0.4–5.5)  3 (0.4–5.5)  0.6 (<0.9)   Estradiol, pM  51.4 (<936)  NE  <18.4 (<37)  NE  NE   Testosterone, nM  NE  0.8(0.1–2.4)  NE  NE  0.1 (0.1–1.1)   GH (basal/peak), μg/L  0.73/70.7a  NE  NE  NE  2.4/14.6b  Age at examination, y:mo  09:01  01:00  05:07  01:08  02:00   IGFBP3, μg/mL  NE  1.02 (1.02–2.05)  NE  NE  NE   IGF-1, ng/mL  91 (133–517)  12 (14–148)  107 (89–357)  19 (32–186)  20 (18–154)  The hormone values above and below the age- and sex-matched reference ranges are in boldface. The numbers, in parentheses, of hormone values indicate reference ranges. Abbreviations: IGFBP3, IGF-binding protein 3. a GH-releasing peptide 2 stimulation at 9 years and 1 month of age. Peak GH responses to GH-releasing peptide 2 in non-GH-deficient short children was 54.4 ± 2.7 ng/mL [Pihoker et al. (5)]. b Arginine stimulation at 2 years of age. View Large Table 2. Hormonal Findings of Our Patients Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Sex  Female  Male  Female  Female  Male  Age at examination, y:mo  15:1  10:9  07:10  2:2  2:4   Calcium, mM  2.37 (2.17–2.55)  2.40 (2.17–2.55)  2.47 (2.17–2.55)  2.71 (2.20–2.65)  2.69 (2.20–2.65)   Inorganic phosphate, mM  1.23 (0.90–1.86)  1.84 (1.22–1.99)  1.58 (1.22–1.99)  1.48 (1.22–1.99)  1.55 (1.22–1.99)   Alkaline phosphatase, IU/L  954 (300–975)  950 (300–975)  631 (300–975)  795 (300–975)  661 (300–975)   Intact PTH, pM  3.7 (1.5–8.3)  4.3 (1.5–8.3)  1.8 (1.5–8.3)  1.1 (1.5–8.3)  1.7 (1.5–8.3)   1,25 (OH)2 vitamin D, pM  157 (48–167)  145 (48–167)  62 (48–167)  156 (48–167)  79 (48–167)   TSH, mIU/L  <0.02 (0.4–4.0)  1.02 (0.4–4.0)  1.25 (0.4–4.0)  2.37 (0.4–4.0)  2.27 (0.4–4.0)   Free T3, pM  5.8 (3.5–6.7)  7.4 (3.9–7.4)  6.2 (3.8–7.0)  6.6 (3.5–6.7)  6.0 (3.5–6.7)   Free T4, pM  17.5 (12.2–23.6)  14.7 (13.0–25.2)  17.1 (13.4–25.9)  14.2 (12.9–24.8)  14.3 (12.9–24.8)   LH, IU/L  2.7 (0.4–6.5)  0.5 (<4.3)  <0.1 (<0.3)  <0.2 (<0.3)  <0.1 (<0.3)   FSH, IU/L  3.4 (0.3–7.8)  1.2 (0.4–3.9)  1.4 (0.4–5.5)  3 (0.4–5.5)  0.6 (<0.9)   Estradiol, pM  51.4 (<936)  NE  <18.4 (<37)  NE  NE   Testosterone, nM  NE  0.8(0.1–2.4)  NE  NE  0.1 (0.1–1.1)   GH (basal/peak), μg/L  0.73/70.7a  NE  NE  NE  2.4/14.6b  Age at examination, y:mo  09:01  01:00  05:07  01:08  02:00   IGFBP3, μg/mL  NE  1.02 (1.02–2.05)  NE  NE  NE   IGF-1, ng/mL  91 (133–517)  12 (14–148)  107 (89–357)  19 (32–186)  20 (18–154)  Patient  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5  Sex  Female  Male  Female  Female  Male  Age at examination, y:mo  15:1  10:9  07:10  2:2  2:4   Calcium, mM  2.37 (2.17–2.55)  2.40 (2.17–2.55)  2.47 (2.17–2.55)  2.71 (2.20–2.65)  2.69 (2.20–2.65)   Inorganic phosphate, mM  1.23 (0.90–1.86)  1.84 (1.22–1.99)  1.58 (1.22–1.99)  1.48 (1.22–1.99)  1.55 (1.22–1.99)   Alkaline phosphatase, IU/L  954 (300–975)  950 (300–975)  631 (300–975)  795 (300–975)  661 (300–975)   Intact PTH, pM  3.7 (1.5–8.3)  4.3 (1.5–8.3)  1.8 (1.5–8.3)  1.1 (1.5–8.3)  1.7 (1.5–8.3)   1,25 (OH)2 vitamin D, pM  157 (48–167)  145 (48–167)  62 (48–167)  156 (48–167)  79 (48–167)   TSH, mIU/L  <0.02 (0.4–4.0)  1.02 (0.4–4.0)  1.25 (0.4–4.0)  2.37 (0.4–4.0)  2.27 (0.4–4.0)   Free T3, pM  5.8 (3.5–6.7)  7.4 (3.9–7.4)  6.2 (3.8–7.0)  6.6 (3.5–6.7)  6.0 (3.5–6.7)   Free T4, pM  17.5 (12.2–23.6)  14.7 (13.0–25.2)  17.1 (13.4–25.9)  14.2 (12.9–24.8)  14.3 (12.9–24.8)   LH, IU/L  2.7 (0.4–6.5)  0.5 (<4.3)  <0.1 (<0.3)  <0.2 (<0.3)  <0.1 (<0.3)   FSH, IU/L  3.4 (0.3–7.8)  1.2 (0.4–3.9)  1.4 (0.4–5.5)  3 (0.4–5.5)  0.6 (<0.9)   Estradiol, pM  51.4 (<936)  NE  <18.4 (<37)  NE  NE   Testosterone, nM  NE  0.8(0.1–2.4)  NE  NE  0.1 (0.1–1.1)   GH (basal/peak), μg/L  0.73/70.7a  NE  NE  NE  2.4/14.6b  Age at examination, y:mo  09:01  01:00  05:07  01:08  02:00   IGFBP3, μg/mL  NE  1.02 (1.02–2.05)  NE  NE  NE   IGF-1, ng/mL  91 (133–517)  12 (14–148)  107 (89–357)  19 (32–186)  20 (18–154)  The hormone values above and below the age- and sex-matched reference ranges are in boldface. The numbers, in parentheses, of hormone values indicate reference ranges. Abbreviations: IGFBP3, IGF-binding protein 3. a GH-releasing peptide 2 stimulation at 9 years and 1 month of age. Peak GH responses to GH-releasing peptide 2 in non-GH-deficient short children was 54.4 ± 2.7 ng/mL [Pihoker et al. (5)]. b Arginine stimulation at 2 years of age. View Large Figure 2. View largeDownload slide (A) Calcium and intact PTH levels in patients 4 and 5. The hormone levels above and below the age- and sex-matched reference ranges are in boldface. NE, not examined. (B) TSH and T3 levels of patient 1. Normal TSH levels: 0.4 to 4.0 mIU/L. Solid line indicates lower limit of the reference TSH levels. The upper and lower limits of the age-matched reference ranges of free T3 are shown by the black broken line and the gray broken line, respectively. m, month; y, year. Figure 2. View largeDownload slide (A) Calcium and intact PTH levels in patients 4 and 5. The hormone levels above and below the age- and sex-matched reference ranges are in boldface. NE, not examined. (B) TSH and T3 levels of patient 1. Normal TSH levels: 0.4 to 4.0 mIU/L. Solid line indicates lower limit of the reference TSH levels. The upper and lower limits of the age-matched reference ranges of free T3 are shown by the black broken line and the gray broken line, respectively. m, month; y, year. Discussion Here, we report five patients with nonmosaic UPD(20)mat. Patients 1 to 5 invariably manifested postnatal growth failure with feeding difficulties and/or low BMI. In addition, most patients showed hypoplastic placenta, oligohydramnios, and delayed bone age. Such clinical features were also documented in previously reported UPD(20)mat cases (3). This phenotype is attributable to deficiency of paternally expressed GNAS transcripts, including XLαs and A/B (6), as mice lacking XLαs on the paternal allele showed poor sucking and postnatal growth failure (7, 8), and animals lacking paternal exon 1A (corresponding to human A/B) exhibited prenatal growth retardation (9). Relative macrocephaly at birth and present appears to be less important in UPD(20)mat than in patients with SRS. Developmental delay of patients 4 and 5 may reflect hypotonia. This may be a transient feature, as four previously reported UPD(20)mat cases exhibited hypotonia in infancy but demonstrated normal development thereafter (3). The association between hypotonia and abnormal expression of GNAS transcripts remains to be clarified. On the other hand, intellectual disability in patient 1 with isodisomy may have been caused by an unmasked autosomal recessive mutation(s). In this study, UPD(20)mat accounted for 5.5% (three of 55) of patients with etiology-unknown SRS and 1.0% (one of 96) of patients with SGA-SS. Patients 1 to 3 met the diagnostic criteria of the Netchine-Harbison clinical scoring system (4), which is currently the most reliable scoring system for SRS, and the remaining two patients exhibited several SRS-compatible features. Moreover, four of five patients were born SGA. These results highlight the clinical significance of UPD(20)mat as a genetic cause of SRS and SGA-SS. In addition, the results for patient 5 indicate that UPD(20)mat can also underlie SS without SGA. Three of four patients with heterodisomy were born to mothers with advanced ages (Table 1). As advanced maternal age increases the risk of aneuploidy in oocyte, and maternal heterodisomy arises from disomic oocyte (Supplemental Fig. 2), advanced maternal age may increase the risk of UPD(20)mat. The most remarkable finding of this study was the endocrinological abnormalities of UPD(20)mat. Hypercalcemia with low or low-normal intact PTH in patients 4 and 5 can be explained by increased sensitivity of the PTH receptor as a result of Gsα overexpression. Likewise, high-normal, free T3 in all patients and low TSH in patient 1 may reflect TSH receptor hypersensitivity. In fact, McCune-Albright syndrome caused by somatic-activating GNAS mutations also manifests as hyperthyroidism (1). As blood TSH levels of patient 1 progressively decreased after 8 years of age, the hormone hypersensitivity associated with UPD(20)mat may gradually develop with age. However, one may argue against UPD(20)mat being responsible for the hormonal abnormalities observed in patients 1 to 5, as blood levels of GH, gonadotropins, and sex hormones were within the normal range, despite the fact that Gsα mediates the signal transduction of the receptor of GH-releasing hormone, LH, and FSH (1). Nevertheless, our results are consistent with previous findings that the imprinting status of the GNAS locus is less strictly regulated in the pituitary and ovary than in the proximal renal tubule and thyroid, and even in the thyroid, the imprinting status varied in individuals (10). Whereas low IGF-1 levels were observed in most of our patients and previously reported cases, this may reflect poor nutrition rather than GH deficiency. Indeed, GH provocative tests in patients 1 and 5 suggested normal GH secretion. As suboptimal GH secretion has been reported in four pseudohypoparathyroidism type 1b patients (11), further studies are necessary to clarify the hormonal characteristics of patients with UPD(20)mat. In summary, the results suggest that UPD(20)mat underlies severe growth failure and feeding difficulties and may account for >5% of cases of SRS of unknown etiology and small percentages of SGA-SS and non-SGA-SS. Most importantly, this study provides an indication that UPD(20)mat is associated with hypersensitivity of Gsα-mediated hormone receptors, which may gradually develop with age. Abbreviations: Abbreviations: BMI body mass index FSH follicle-stimulating hormone GH growth hormone GNAS guanine nucleotide binding protein, alpha stimulating Gsα α-subunit of the stimulatory G protein IGF-1 insulinlike growth factor 1 LH luteinizing hormone OFC occipitofrontal circumference PTH parathyroid hormone SDS standard deviation score SGA-SS small for gestational age-short stature SRS Silver-Russell syndrome T3 triiodothyronine T4 thyroxine TSH thyroid-stimulating hormone UPD(20)mat maternal uniparental disomy for chromosome 20 XLαs extra large form of Gsα Acknowledgments We thank the patients and their family members for their cooperation. We also thank Ms. Shigeko Honjyo for her support in collecting clinical information. Financial Support: This work was supported by grants from the Japan Society for the Promotion of Science (JSPS; 15K15096 and 17H06428), National Center for Child Health and Development (28-6), Japan Agency for Medical Research and Development (AMED; 17ek0109278h0001, 16ek0109030h0003, and 16ek0109141h0002), the Takeda Science Foundation, and Japanese Society for Pediatric Endocrinology Future Development Grant. Disclosure Summary: The authors have nothing to disclose. References 1. Turan S, Bastepe M. GNAS spectrum of disorders. Curr Osteoporos Rep . 2015; 13( 3): 146– 158. Google Scholar CrossRef Search ADS PubMed  2. Takatani R, Minagawa M, Molinaro A, Reyes M, Kinoshita K, Takatani T, Kazukawa I, Nagatsuma M, Kashimada K, Sato K, Matsushita K, Nomura F, Shimojo N, Jüppner H. Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B). Bone . 2015; 79: 15– 20. Google Scholar CrossRef Search ADS PubMed  3. Mulchandani S, Bhoj EJ, Luo M, Powell-Hamilton N, Jenny K, Gripp KW, Elbracht M, Eggermann T, Turner CL, Temple IK, Mackay DJ, Dubbs H, Stevenson DA, Slattery L, Zackai EH, Spinner NB, Krantz ID, Conlin LK. Maternal uniparental disomy of chromosome 20: a novel imprinting disorder of growth failure. Genet Med . 2016; 18( 4): 309– 315. Google Scholar CrossRef Search ADS PubMed  4. Azzi S, Salem J, Thibaud N, Chantot-Bastaraud S, Lieber E, Netchine I, Harbison MD. A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome. J Med Genet . 2015; 52( 7): 446– 453. Google Scholar CrossRef Search ADS PubMed  5. Pihoker C, Middleton R, Reynolds GA, Bowers CY, Badger TM. Diagnostic studies with intravenous and intranasal GHRP-2 in children of short stature. J Clin Endocrinol Metab . 1995; 80( 10): 2987– 2992. Google Scholar PubMed  6. Geneviève D, Sanlaville D, Faivre L, Kottler ML, Jambou M, Gosset P, Boustani-Samara D, Pinto G, Ozilou C, Abeguilé G, Munnich A, Romana S, Raoul O, Cormier-Daire V, Vekemans M. Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties. Eur J Hum Genet . 2005; 13( 9): 1033– 1039. Google Scholar CrossRef Search ADS PubMed  7. Plagge A, Gordon E, Dean W, Boiani R, Cinti S, Peters J, Kelsey G. The imprinted signaling protein XL α s is required for postnatal adaptation to feeding. Nat Genet . 2004; 36( 8): 818– 826. Google Scholar CrossRef Search ADS PubMed  8. Xie T, Plagge A, Gavrilova O, Pack S, Jou W, Lai EW, Frontera M, Kelsey G, Weinstein LS. The alternative stimulatory G protein α-subunit XLalphas is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice. J Biol Chem . 2006; 281( 28): 18989– 18999. Google Scholar CrossRef Search ADS PubMed  9. Ball ST, Kelly ML, Robson JE, Turner MD, Harrison J, Jones L, Napper D, Beechey CV, Hough T, Plagge A, Cattanach BM, Cox RD, Peters J. Gene dosage effects at the imprinted Gnas cluster. PLoS One . 2013; 8( 6): e65639. Google Scholar CrossRef Search ADS PubMed  10. Mantovani G, Ballare E, Giammona E, Beck-Peccoz P, Spada A. The gsalpha gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab . 2002; 87( 10): 4736– 4740. Google Scholar CrossRef Search ADS PubMed  11. Sano S, Iwata H, Matsubara K, Fukami M, Kagami M, Ogata T. Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib. Endocr J . 2015; 62( 6): 523– 529. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society

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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Mar 14, 2018

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