Bochukova et al. (2012) described a 6-year-old girl, born of unrelated parents of white European origin, who presented with growth retardation. At 18 months of age, her height was in the tenth percentile, and the deficit persisted; in ... Bochukova et al. (2012) described a 6-year-old girl, born of unrelated parents of white European origin, who presented with growth retardation. At 18 months of age, her height was in the tenth percentile, and the deficit persisted; in addition, she had decreased subischial leg length with a normal sitting height. Tooth eruption was delayed: she had no teeth at 12 months of age, only 8 deciduous teeth at 26 months, and no secondary dentition at 6 years of age. She had a borderline-high body mass index (23.5), and severe constipation had been noted since weaning at the age of 7 months. Mild hypermobility and ligamentous laxity was present in the ankle and knee. Muscle tone was reduced with normal power but with impairment in gross and fine motor coordination, resulting in a slow broad-based gait, clumsiness, and difficulty with fine motor skills, including an inability to write or draw. Her affect was placid, with slow monotonous speech, but with no receptive or expressive deficit. Neuropsychologic assessment showed restricted adaptive behavior and significant impairments in selected cognitive domains. Laboratory analysis revealed low-normal or subnormal levels of total thyroxine and free thyroxine, high-normal or elevated levels of total triiodothyronine and free triiodothyronine, and normal levels of thyroid stimulating hormone (TSH), resulting in markedly subnormal ratios of free thyroxine to free triiodothyronine and of total thyroxine to total triiodothyronine with a very low level of circulating reverse triiodothyronine. The level of serum thyroxine-binding globulin was normal. Skeletal radiographs showed delayed fusion of cranial sutures with a patent anterior fontanel, multiple wormian bones, and delayed tooth eruption, together with femoral epiphyseal dysgenesis and delayed bone age (chronologic age, 6.3 years; bone age, 2.9 years). Abdominal radiography revealed bowel dilatation with abnormal retention of ingested marker pellets, confirming delayed intestinal transit. The child had a low resting heart rate and blood pressure, of 71 bpm and 82/51 mmHg, respectively, as well as basal metabolic rate (BMR) that was below normal. However, the level of serum sex hormone-binding globulin (SHBG; 182205), a hepatic marker of thyroid hormone action, was markedly elevated, and a normal growth hormone (139250) response to provocative testing was associated with slightly subnormal levels of insulin-like growth factor (IGF1; 147440). Thyroid replacement therapy led to normalization of free thyroxine, free triiodothyronine, and IGF1, with full suppression of TSH and normalization of her BMR, but she continued to have a high level of sex hormone-binding globulin, and her pulse rate and blood pressure remained abnormally low, as did the growth rate and intestinal transit time. Van Mullem et al. (2012) reported a father and daughter with congenital hypothyroidism. The daughter was an 11-year-old girl who in the first 3 years of life had macroglossia, omphalocele, congenital hip dislocation, no hip ossification centers, delayed closure of skull sutures, delayed tooth eruption, delayed motor development, and macrocephaly. She had low levels of free thyroxine (T4) with normal levels of TSH. Evaluation at 6 years of age for short stature showed delayed bone age, and she was found to have low-normal IGF1 and high cholesterol levels in addition to abnormal levels of thyroid hormone. Hypothyroidism was clinically apparent, with dry skin, slow tendon reflexes, slow reactions, and drowsiness. Treatment with levothyroxine resulted in initial catch-up growth and decreases in serum levels of TSH and cholesterol. At 8.5 years of age, her height remained 2 SD below normal, and treatment with growth hormone had little effect. At 11 years of age, her bone age was 9 years and her height was 1.81 SD below normal; she also had mild cognitive deficits with an IQ of 90. Her father had very similar characteristics, including short stature (3.77 SD below normal), free T4 in the low-normal range, high T3, and normal TSH, high cholesterol levels, IGF1 in the low-normal range, suppressed growth hormone stimulation, and mild cognitive deficits (IQ, 85). Both father and daughter had constipation when not receiving levothyroxine.
In a 6-year-old girl with congenital nongoitrous hypothyroidism, Bochukova et al. (2012) performed whole-exome sequencing and identified a de novo heterozygous nonsense mutation in the THRA gene (190120.0001) that generates a mutant protein that inhibits wildtype receptor action ... In a 6-year-old girl with congenital nongoitrous hypothyroidism, Bochukova et al. (2012) performed whole-exome sequencing and identified a de novo heterozygous nonsense mutation in the THRA gene (190120.0001) that generates a mutant protein that inhibits wildtype receptor action in a dominant-negative manner. In a father and daughter with congenital nongoitrous hypothyroidism, van Mullem et al. (2012) identified heterozygosity for a 1-bp insertion in the THRA gene (190120.0002) that was not found in more than 300 Caucasian controls or in public databases. Mutations in 6 other thyroid-related genes were excluded by sequence analysis.