Phenotype-Genotype Correlations of GH1 Gene Variants in Patients with Isolated Growth Hormone Deficiency or Multiple Pituitary Hormone Deficiency.

INTRODUCTION: Genetic forms of growth hormone deficiency (GHD) may occur as isolated GHD (IGHD) or as a component of multiple pituitary hormone deficiency (MPHD). This study aimed to present the clinical and molecular characteristics of patients with IGHD/MPHD due to the GH1 gene variants. METHODS: A gene panel accommodating 25 genes associated with MPHD and short stature was used to search for small sequence variants. Multiplex ligation-dependent probe amplification was performed in patients with normal panel results to investigate gross deletion/duplications. Segregation in the family was performed by Sanger sequencing. RESULTS: The GH1 gene variants were detected in 5 patients from four unrelated families. One patient had IGHD IA due to homozygous whole GH1 gene deletion and one had IGHD IB due to novel homozygous c.162C>G/p.(Tyr54*) variant. Two patients from a family had previously reported heterozygous c.291+1G>A/p.(?) variant in which clinical and genetic characteristics were compatible with IGHD II accompanying MPHD. One patient had clinical and laboratory characteristics of IGHD II with MPHD but the heterozygous c.468 C>T/p.(R160W) variant had conflicting results about the relationship with the phenotype. CONCLUSION: Expanding our knowledge of the spectrum of GH1 gene variants by apprehending clinical and molecular data of more cases, helps to identify the genotype-phenotype correlation of IGHD/MPHD and the GH1 gene variants. These patients must be regularly followed up for the occurrence of additional pituitary hormone deficiencies.

Phenotypic features of RETREG1-related hereditary sensory autonomic neuropathy.

BACKGROUND AND AIMS: Homozygous loss-of-function mutations in the RETREG1 gene result in Hereditary Sensory Autonomic Neuropathy Type 2B. Clinical features include pain loss, autonomic disturbances, and upper motor neuron features. METHODS: We evaluated the clinical and genetic features of seven patients from four families with RETREG1 variants. RESULTS: Five patients were male. The median age of disease onset was 7.00 ± 2.81 (between 2 and 10 years). A combination of painless wounds, trophic changes, and foot ulcerations was the presenting symptom in five patients and walking difficulties in two. Motor symptoms were present in five patients. In a median disease duration of 30.00 ± 12.88 years, five patients had osteomyelitis, and three had toe amputations. A history of renal disease was present in one family. In another family, three affected siblings had short stature and a history of delayed puberty. Although sensory signs predominated the clinical findings, various degrees of motor signs such as muscle weakness, spasticity, and brisk tendon reflexes were noted in all patients. Nerve conduction studies showed axonal sensory-motor neuropathy in five patients and sensory neuropathy in two. Three pathogenic variants were identified in the RETREG1 gene. Two unrelated patients had a homozygous c.433C > T/p.(Gln145*), one a homozygous c.826delA/p.(Ser276Valfs*8), and the last had a novel homozygous c.102delC/p.(Ala35Glnfs*349) variants. INTERPRETATION: In our study, all patients showed signs and symptoms consistent with pain insensitivity. Although shadowed by sensory symptoms, motor signs were noted in our patients. Further studies are necessary to clarify the causal relationship between extra-neurological features and RETREG1 mutations.