Biallelic POC1A variants cause syndromic severe insulin resistance with muscle cramps

Abstract

Objective: To describe clinical, laboratory, and genetic characteristics of three unrelated cases from Chile, Portugal, and Saudi Arabia with severe insulin resistance, SOFT syndrome, and biallelic pathogenic POC1A variants.

Design: Observational study.

Methods: Probands' phenotypes, including short stature, dysmorphism, and insulin resistance, were compared with previous reports.

Results: Cases 1 (female) and 3 (male) were homozygous for known pathogenic POC1A variants: c.649C>T, p.(Arg217Trp) and c.241C>T, p.(Arg81*), respectively. Case 2 (male) was compound heterozygous for p.(Arg217Trp) variant and the rare missense variant c.370G>A, p.(Asp124Asn). All three cases exhibited severe insulin resistance, acanthosis nigricans, elevated serum triglycerides and decreased HDL, and fatty liver, resembling three previously reported cases. All three also reported severe muscle cramps. Aggregate analysis of the six known cases with biallelic POC1A variants and insulin resistance showed decreased birth weight and length mean (s.d.): -2.8 (0.9) and -3.7 (0.9) SDS, respectively), severe short stature mean (s.d.) height: -4.9 (1.7) SDS) and moderate microcephaly (mean occipitofrontal circumference -3.0 (range: -4.7 to -1.2)). These findings were similar to those reported for patients with SOFT syndrome without insulin resistance. Muscle biopsy in Case 3 showed features of muscle involvement secondary to a neuropathic process.

Conclusions: Patients with SOFT syndrome can develop severe dyslipidaemic insulin resistance, independent of the exonic position of the POC1A variant. They also can develop severe muscle cramps. After diagnosis, patients should be regularly screened for insulin resistance and muscle complaints.

Figure 1

Case 1. (A) Pedigree (using INVITAE Family pedigree tool). M/M indicates a biallelic POC1A variant, M/W a heterozygous carrier. (B) Growth curve (height for age) against CDC chart. (C and D) Frontal and lateral photographs aged 8.8 years. (E) Chest at 8.8 years showing the café au lait spot. (F) Hands show brachydactyly and mild fifth finger clinodactyly and broad thumbs. The nails were broad and short. (G) Feet show broad big toes. (H) Broad upper legs. (I) Muscle cramps aged 21.5 years. (J) Scalp aged 21.5 years. (K) The hand X-ray aged 8.7 years shows short phalanges, cone epiphyses of the distal phalanges, pseudo-epiphysis in the middle phalanx of the index, clinodactyly of the little finger, and a slight delay in bone maturation. (L) The pelvic X-ray aged 8.7 years shows asymmetric involvement of the femoral necks with abnormal remodelling, shortening, and deformity.

Figure 2

Case 2. (A) Pedigree (using INVITAE Family pedigree tool). M/M indicates a biallelic POC1A variant, M/W a heterozygous carrier. (B) Height plotted against CDC charts. (C, D, E, and F) Frontal and lateral photographs aged 22.3 years.

Figure 3

Case 3. (A) Family pedigree (using INVITAE Family pedigree tool). M/M indicates a biallelic POC1A variant, M/W a heterozygous carrier. (B) Clinical features demonstrating the abnormal findings: (i) short stature; (ii) high forehead and frontal bossing; (iii) posterior low set ear; (iv) gynaecomastia; (v) Acanthosis nigricans; (vi) hypoplastic distal phalanges and nails; (vii) wide space between big and second toes. (C) Radiological abnormalities: (i) short third metacarpal; (ii) metatarsal bone; (iii) short femoral neck; (iv) empty sella turcia.