Obesity, Hyperphagia, And Developmental Delay

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2019-09-22
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A number sign (#) is used with this entry because of evidence that obesity, hyperphagia, and developmental delay (OBHD) is caused by heterozygous mutation in the NTRK2 gene (600456) on chromosome 9q21.

Description

OBHD is a neurodevelopmental disorder characterized by global developmental delay and hyperphagia resulting in obesity. Some patients may develop seizures (summary by Hamdan et al., 2017).

Clinical Features

Yeo et al. (2004) reported an 8-year-old boy from the United Kingdom with early-onset obesity, hyperphagia, and severe developmental delay. Although the patient had a normal birth weight, he rapidly gained weight from age 6 months, and his body mass index (BMI) was 3.5 SD above normal by age 8 years. Fasting plasma insulin was not markedly elevated and thyroid function tests were normal. There were no dysmorphic features. He demonstrated hyperphagia similar to individuals with congenital leptin deficiency (see 164160). He also had severe developmental delay in motor function, speech, and language, and demonstrated a blunted response to nociceptive stimuli. He had absence seizures in the second and third years of life only. Yeo et al. (2004) noted the phenotypic similarities between their patient and the mouse model of TrkB deficiency reported by Xu et al. (2003).

Miller et al. (2017) studied a 7.5-year-old girl (family 37) with a history of hyperphagia who was overweight (body mass index, 25.3) and had moderate learning difficulties with speech and language delay, as well as progressive onset of aggressive outbursts and ritualized behaviors. Oral glucose tolerance test was normal; ultrasound showed streak ovaries and uterus. When she was 1 year of age, facial asymmetry was noted; 3D-CT scan revealed left coronal synostosis, which was repaired.

Hamdan et al. (2017) reported an 11-year-old girl (HSJ0335), born of unrelated parents from Guatemala, with OBHD. She presented with global developmental delay and poor growth at 4 months of age. She began walking with a clumsy and unsteady gait at age 3. She had poor language development and autistic features. Between 2 and 9 years of age, she developed generalized seizures that were difficult to control, including episodes of status epilepticus. Around age 3, she became hyperphagic and gained weight, resulting in obesity. She had poor eye contact and stereotypic movements. Brain imaging showed delayed myelination, enlarged ventricles, thin corpus callosum, and reduced white matter volume.

Molecular Genetics

In an 8-year-old British boy with early-onset obesity, hyperphagia, and severe developmental delay, who was negative for mutation in the LEP (164160), LEPR (601007), POMC (176830), and MC4R (155541) genes, Yeo et al. (2004) sequenced the TRKB (NTRK2) gene and identified heterozygosity for a de novo missense mutation (Y722C; 600456.0001) that was not found in 192 ethnically matched alleles. Sequencing of the NTRK2 gene in 288 individuals with severe early-onset obesity and developmental delay revealed 5 patients who each carried a different heterozygous missense variant, none of which were found in 192 ethnically matched alleles. Yeo et al. (2004) considered those observations to be preliminary, pending cosegregation analysis and functional studies.

In a cohort of 40 patients with craniosynostosis in whom routine molecular testing was negative, Miller et al. (2017) performed exome sequencing and identified a 7.5-year-old girl (family 37) with hyperphagic obesity, developmental delay, and craniosynostosis who was heterozygous for a nonsense mutation in the NTRK2 gene (G444X; 600456.0002).

In an 11-year-old girl (HSJ0335), born of unrelated parents from Guatemala, with OBHD, Hamdan et al. (2017) identified a de novo heterozygous missense mutation in the NTRK2 gene (T720I; 600456.0004). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed, but Hamdan et al. (2017) noted that the mutation was adjacent to another mutation reported in a patient with a similar phenotype (Y722C; 600456.0001).