Neurologic, Endocrine, And Pancreatic Disease, Multisystem, Infantile-Onset

A number sign (#) is used with this entry because of evidence that infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) is caused by homozygous mutation in the PTRH2 gene (608625) on chromosome 17q23.

Description

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) is an autosomal recessive multisystemic disorder with variable expressivity. The core features usually include global developmental delay with impaired intellectual development and speech delay, ataxia, sensorineural hearing loss, and pancreatic insufficiency. Additional features may include peripheral neuropathy, postnatal microcephaly, dysmorphic facial features, and cerebellar atrophy. However, some patients may not display all features (summary by Picker-Minh et al., 2016, Sharkia et al., 2017).

Clinical Features

Hu et al. (2014) reported 2 sibs, born of consanguineous Turkish parents, with a progressive multisystem disease first apparent at birth. The patients were born at term with normal growth parameters, including normal head circumference; 1 had decreased fetal movements in utero. At birth, the infants were noted to have hip dislocation, hypotonia, brachycephaly, mild facial dysmorphism with midface hypoplasia, hypertelorism, exotropia, thin upper lip vermilion, proximally placed thumbs, and deformities of the fingers and toes; the boy had a shawl scrotum. Both patients developed postnatal microcephaly, failure to thrive with growth retardation, delayed motor milestones, progressive ataxia, distal muscle weakness with ankle contractures, demyelinating sensorimotor neuropathy, and sensorineural deafness. The patients had moderate intellectual disability with severe expressive speech delay and short stature. One patient became wheelchair-bound by age 15 years. Brain imaging showed microencephaly and progressive cerebellar atrophy. Additional features included hypothyroidism, exocrine pancreatic insufficiency with bulky steatorrhea, deficiency of lipophilic vitamins, and abnormal clotting parameters. These abnormalities normalized with supplementation of pancreatic enzymes. One patient had mildly elevated glucose levels, suggesting pancreatic endocrine abnormalities. Ultrasound showed evidence of hepatic and pancreatic fibrosis and hepatomegaly.

Alazami et al. (2015) reported a 10-year-old boy, born of consanguineous parents, with global developmental delay, hypotonia, hearing loss, ataxia, hyporeflexia, and clubfoot. There was no mention of endocrine or pancreatic exocrine abnormalities. A brother was similarly affected.

Picker-Minh et al. (2016) reported 5 patients from 2 unrelated consanguineous families of Tunisian and Saudi Arabian descent with IMNEPD. All carried the same homozygous missense mutation in the PTRH2 gene (Q85P; 608625.0002). One patient was a sporadic case, and 4 came from a single kindred. Although there was some phenotypic variability, even within the family, most patients had global developmental delay with impaired intellectual development, motor delay, speech delay, sensorineural hearing loss, and ataxia. Most also had exocrine pancreatic insufficiency, often associated with early failure to thrive. Only 1 patient, the sole Tunisian patient, also had pancreatic endocrine insufficiency with diabetes mellitus and liver involvement with hepatomegaly and steatosis. Some patients had dysmorphic facial features, including midface hypoplasia, thin upper lip vermilion, exotropia, and ptosis. Other features, including facial palsy, distal muscle atrophy and weakness, truncal hypotonia, dysmetria, peripheral demyelinating neuropathy, and cerebellar atrophy, were only occasionally present.

Sharkia et al. (2017) reported 3 sisters, born of consanguineous Arab parents, with IMNEPD. The patients were 17, 15, and 13 years of age at the time of the report. They had severe sensorimotor peripheral neuropathy resulting in delayed motor development, distal muscle weakness and atrophy affecting the upper and lower limbs, difficulty walking, pes cavus, and impaired fine motor skills. They also had sensorineural hearing loss with impaired expressive language, although cognition was normal. Other features included mild microcephaly, myopia, and mildly delayed puberty. Brain imaging and metabolic screening were normal. None of the sisters had ataxia, pancreatic insufficiency, hypothyroidism, or liver involvement. The report expanded the phenotypic spectrum of the disorder.

Le et al. (2019) reported 3 brothers, born of consanguineous Syrian parents, with IMNEPD. The patients were 27, 17, and 7 years of age at the time of the report. The oldest sib was the most severely affected: he lost vocalization at age 1 year, lost independent ambulation at 14 months due to progressive ataxia and muscle weakness, and developed generalized and myoclonic seizures at age 7 years. Other features included contractures of the hands and feet, postnatal microcephaly, dysmorphic facial features, sensorimotor axonal and demyelinating polyneuropathy, and hearing impairment. His brothers also showed global developmental delay and impaired intellectual development with poor speech, microcephaly, trunk and limb ataxia, hypotonia, and distal muscle weakness and atrophy. The 2 older sibs had diabetes mellitus, and all sibs had seizures. Brain imaging showed cerebellar atrophy in the 2 older sibs. The 2 younger sibs did not have hearing impairment; pancreatic exocrine insufficiency was not mentioned in the report.

Inheritance

The transmission pattern of IMNEPD in the family reported by Hu et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous Turkish parents, with infantile-onset multisystem neurologic, endocrine, and pancreatic disease, Hu et al. (2014) identified a homozygous truncating mutation in the PTRH2 gene (608625.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Patient cells showed decreased cell viability when stressed, which could be rescued by expression of wildtype PTRH2. Patient cells also showed decreased activation of the FAK (PTK2; 600758) and mTOR (601231) pathways, and increased phosphorylation of ERK (see 610795). The findings suggested a role for PTRH2 in postmitotic cell growth and survival.

Alazami et al. (2015) identified a homozygous missense mutation in the PTRH2 gene (Q85P; 608625.0002) in a 10-year-old boy with global developmental delay, hypotonia, hearing loss, and ataxia. The patient was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the PTRH2 variant were not performed.

Picker-Minh et al. (2016) identified a homozygous Q85P mutation in 5 patients from 2 unrelated highly consanguineous kindreds of Tunisian and Saudi Arabian descent with IMNEPD. Fibroblasts derived from 1 of the patients showed normal PTRH2 mRNA levels, but decreased protein levels.

Sharkia et al. (2017) identified a homozygous Q85P mutation in 3 sibs, born of consanguineous Arab parents, with IMNEPD. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. Clinical variability was observed.

In 3 sibs, born of consanguineous Syrian parents, with IMNEPD, Le et al. (2019) identified a homozygous nonsense mutation in the PTRH2 gene (W108X; 608625.0003). Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a truncated protein lacking most of the enzymatic active site, causing a loss of function.

Genotype/Phenotype Correlations

Picker-Minh et al. (2016), Sharkia et al. (2017), and Le et al. (2019) observed that patients with frameshift or nonsense PTRH2 mutations tended to have a more severe phenotype than those with the missense mutation Q85P, which is common among individuals from the Middle East.

Animal Model

Kairouz-Wahbe et al. (2008) found that Bit1 (Ptrh2)-null mice were born alive, but they died within the first 2 weeks from a runting syndrome with muscle weakness, ataxia, and decreased weight. Cultured mouse embryonic fibroblasts (MEFs) from Bit1-null embryos were more resistant to cell death induced by anoikis than cells from wildtype or heterozygous littermates. MEFs and tissues from Bit1-null mice displayed a marked increase in Erk phosphorylation. Knockdown of BIT1 expression in HeLa cells resulted in increased ERK activation, and partially knocking down ERK2 reversed the increased anoikis resistance of BIT1 knockdown.

Hu et al. (2014) found that Ptrh2-null mice showed progressive muscle weakness and wasting, ataxia, cerebellar atrophy, and decreased neuronal size in the cerebral cortex. Mutant mice also had insufficient exocrine pancreatic function. Molecular studies showed a reduction in integrin-mediated signaling, with decreased Bcl2 (151430) expression, as well as an increase in Erk phosphorylation.