Maternal uniparental disomy 14 in a 15‐year‐old boy with normal karyotype and no evidence of precocious puberty

During the past 13 years, 24 patients with complete maternal UPD of chromosome 14 (mUPD14) have been described [for review see Berends et al., 1999; Hordijk et al., 1999; Kotzot, 1999; Sanlaville et al., 2000; Sutton and Shaffer, 2000]. Although the condition is associated with a phenotype pattern distinct from other syndromes, including paternal UPD14, most of the characteristic features are variably expressed and not specific. In particular, a clinical overlap with Prader–Willi syndrome (PWS) is evident. Thus, it is reasonable to assume that a considerable number of cases are overlooked and classified as unclear malformation syndromes or misdiagnosed as PWS with unidentified mutation, respectively. Here, we report on a boy with mUPD14 who has a normal karyotype and no evidence of premature puberty. The patient was referred to our genetic counseling unit by his parents because of rapidly increasing weight and an unexplained growth arrest. He is the only child of healthy, unrelated parents. The mother had two miscarriages in early pregnancy at 29 and 31 years of age, shewas 35 years old at the time of the patient’s birth. The pregnancy was uneventful, delivery took place at the 42nd week of gestation by cesarean section due to delivery arrest. Birth weight was 2,880 g (3rd centile), length was 53 cm (50th centile), and head circumference was 38 cm (90th centile). A hydrocephalus was ruled out by ultrasound. The postnatal period was characterized by prolonged hypotonia along with poor sucking, the early motor developmental milestones and the speech were delayed. From early childhood onwards, the statomotoric development has been delayed, the boy is presently unable to ride a bicycle. The body weight was normal until 4 years of age, thereafter it increased slowly. Rapidweight gainwas noticed at about 13–14 years of age, the appetite of the boy was described as normal. The height was normal until about 13 years of age, thereafter a growth arrest became obvious. Puberty started at 12 years of age and proceeded rapidly, he started shaving at 13 years of age. The patient is described as quiet and passive, he first attended grammar school, but changed school due to obvious social problems and reduced ability in some subjects. Laboratory examinations showed normal values for routine parameters including cholesterol. Endocrinological results: Cortisol excretion in 24-hr urine, dexamethasone suppression test, 17-OH progesterone, DHEAS, TSH, T4, free-T4, free-T3, oral glucose tolerance test, and HbA(1c) were normal. Androstendion (1.92 ng/ml; normal value 1.2 ng/ml) and testosterone (8.8 ng/ml) were slightly elevated. IGF-1 was 225 ng/ml (1st–5th centile), IGF BP-3 was 3.09 mg/L (30th– 50th centile). In a carporadiogram conducted at age 15, the boneage (according toGreulichandPyle) appearedaccelerated (18 years). Echocardiography and ultrasound of the abdomen were normal. Physical examination: 15-year-old lethargic boy with a weight of 81.5 kg (>97th centile) and predominant truncal obesity (Fig. 1). The height was 167 cm (25th centile), i.e., it remained significantly below the target height of 187 cm. According to the accelerated bone age no relevant further increase in height was expected. He showed macrocephaly with a head circumference of 60 cm (>97th centile). However, the head circumference of his father (61 cm) points to a familial background. The length of the hands was 16 cm (3rd centile). Mild dysmorphic signs include prominent forehead, broad nasal root, fleshy nasal tip, short philtrum, slightly downslanting palpebral fissures, and slightly posteriorly rotated auricles (Fig. 1). Testes were descended, puberty stage was D4T4 (Tanner stage). Chromosomal analysis was normal (50 cells). Prader–Willi syndrome was unlikely since he did not fulfil the diagnostic criteria [Gunay-Aygun et al., 2001]. The parental origin of chromosome 14 was examined by analyzing 10 microsatellite markers spanning the whole chromosome. Seven of the markers were informative and confirmed mUPD14. Three of the markers show maternal heterodisomy and two maternal isodisomy, reflecting recombination during meiosis. Biparental inheritance of other chromosomes was confirmed. There was no evidence of non-paternity, and no evidence of low-level mosaic trisomy 14. The most striking and consistent clinical features of mUPD14 include abnormalities in growth (intrauterine growth retardation, low birth weight, short stature, small hands), truncal obesity, hypotonia along with feeding problems, mild to moderate psychomotor developmental delay, precocious puberty, and mild facial dysmorphisms. Several other findings (scoliosis, joint laxity, transient hydrocephaly/ macrocephaly, recurrent otitis media, diabetes mellitus) were observed less frequently. Most of the patients have normal intelligence or only mild mental delay. Nevertheless, the clinical spectrum of mUPD14 is variable, even the most prominent manifestations are not always present. Only premature or early puberty—starting usually between 8 and 10 years of age and mostly accompanied by accelerated bone age—was described in almost all symptomatic patients old enough to determine the age of onset and is considered to be a constant feature. The present case shares several of the key findings in mUPD14. Nonetheless, the manifestation of the complete phenotype with rapid weight gain and growth arrest was delayed until 13–14 years of age. Obesity seems to be an important, but age dependent symptom in mUPD14. In contrast to PWS and in accordance with our and several other patients, rapidweight gain develops usually later in childhood: in mUPD14 it was observed altogether in only 40%–60%; however, almost all patients diagnosed at 7 years of age or later were reported to be obese while the symptomwas not observed in children younger than 7 years of age [Berends et al., 1999; Hordijk et al., 1999; Sanlaville et al., 2000; Cox et al., 2004] (Table I). Unlike nearly all cases reported so far, premature puberty was absent in our patient. Although it was described as having been passed through rapidly, puberty started within the normal range. There is only one description of a female with *Correspondence to: Stefan Aretz, M.D., Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany. E-mail: Stefan.Aretz@ukb.uni-bonn.de