Biallelic POC1A variants cause syndromic severe insulin resistance with muscle cramps.

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.

Primary Ovarian Failure in Addition to Classical Clinical Features of Coats Plus Syndrome in a Female Carrying 2 Truncating Variants of CTC1.

Coats plus syndrome is an autosomal recessive multisystemic and pleiotropic disorder affecting the eyes, brain, bone, and gastrointestinal tract, usually caused by compound heterozygous variants of the conserved telomere maintenance component 1 gene (CTC1), involved in telomere homeostasis and replication. So far, most reported patients are compound heterozygous for a truncating mutation and a missense variant. The phenotype is believed to result from telomere dysfunction, with accumulation of DNA damage, cellular senescence, and stem cell depletion. Here, we report a 23-year-old female with prenatal and postnatal growth retardation, microcephaly, osteopenia, recurrent fractures, intracranial calcification, leukodystrophy, parenchymal brain cysts, bicuspid aortic valve, and primary ovarian failure. She carries a previously reported maternally inherited pathogenic variant in exon 5 (c.724_727del, p.(Lys242Leufs*41)) and a novel, paternally inherited splice site variant (c.1617+5G>T; p.(Lys480Asnfs*17)) in intron 9. CTC1 transcript analysis showed that the latter resulted in skipping of exon 9. A trace of transcripts was normally spliced resulting in the presence of a low level of wild-type CTC1 transcripts. We speculate that ovarian failure is caused by telomere shortening or chromosome cohesion failure in oocytes and granulosa cells, with early decrease in follicular reserve. This is the first patient carrying 2 truncating CTC1 variants and the first presenting primary ovarian failure.

Intrauterine Twin Discordancy and Partial Postnatal Catch-up Growth in a Girl with a Pathogenic IGF1R Mutation

Objective: Insulin like growth factors-1 (IGF-1) is essential for normal in utero and postnatal human growth. It mediates its effects through the IGF-1 receptor (IGF1R), a widely expressed cell surface tyrosine kinase receptor. The aim of the study was to analyze pre- and post-natal growth, clinical features and laboratory findings in a small for gestational age (SGA) girl in whom discordant postnatal growth persisted and her appropriate for gestational age (AGA) brother. Methods: A girl born with a low weight and length [-2.3 and -2.4 standard deviation (SD) score (SDS), respectively] but borderline low head circumference (-1.6 SD) presented with a height of -1.7 SDS, in contrast to a normal height twin brother (0.0 SDS). IGF-1 resistance was suspected because of elevated serum IGF-1 levels. Results: Sequencing revealed the presence of a previously described pathogenic heterozygous mutation (p.Glu1050Lys) in the SGA girl which was not present in the parents nor in the AGA twin brother. Conclusion: The pathogenic IGF1R mutation in this girl led to intrauterine growth retardation followed by partial postnatal catch-up growth. Height in mid-childhood was in the lower half of the reference range, but still 1.7 SD shorter than her twin brother.

Clinical and genetic characteristics and effects of long-term growth hormone therapy in a girl with Floating-Harbor syndrome.

The established facts to date relating to Floating-Harbor syndrome (FHS) are its characteristic typical triangular facies with bulbous nose and thin lips, short stature, delayed bone age, and mild mental retardation with delay in expressive speech; its sporadic occurrence without Mendelian inheritance; and its unknown cause. Little is known about the growth hormone-insulin-like growth factor 1 (GH-IGF-1) axis and the effect of GH treatment in children with this syndrome. We report on a 9-year-old girl born small for gestational age (SGA, birth length -2.2 standard deviation score) with persistent short stature who has been treated with GH from 3.5 years onward with a modest growth response. Revision of the case led to the diagnosis of FHS. No abnormalities were found in the sequence or copy number of IGF-1 receptor or in the genomic single-nucleotide polymorphism array. GH treatment led to an increase in serum IGF-1 in the upper normal range, but the growth response was modest, suggesting a defect in IGF-1 signaling. Early recognition of this entity is important, as it enables specific diagnostic tests targeted at other abnormalities associated with FHS.

Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences.

The majority of insulin-like growth factor (IGF)-I and IGF-II circulate in the serum as a complex with the insulin-like growth factor binding protein (IGFBP)-3 or IGFBP-5, and an acid-labile subunit (ALS). The function of ALS is to prolong the half-life of the IGF-I-IGFBP-3/IGFBP-5 binary complexes. Fourteen different mutations of the human IGFALS gene have been identified in 17 patients, suggesting that ALS deficiency may be prevalent in a subset of patients with extraordinarily low serum levels of IGF-I and IGFBP-3 that remain abnormally low upon growth hormone stimulation. Postnatal growth was clearly affected. Commonly, the height standard deviation score before puberty was between -2 and -3, and approximately 1.4 SD shorter than the midparental height SDS. Pubertal delay was found in 50% of the patients. Circulating IGF-II, IGFBP-1, -2 and -3 levels were reduced, with the greatest reduction observed for IGFBP-3. Insulin insensitivity was a common finding, and some patients presented low bone mineral density. Human ALS deficiency represents a unique condition in which the lack of ALS proteins results in the disruption of the entire IGF circulating system. Despite a profound circulating IGF-I deficiency, there is only a mild impact on postnatal growth. The preserved expression of locally produced IGF-I might be responsible for the preservation of linear growth near normal limits.

Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect.

OBJECTIVES: To investigate in an open-label randomized study, the effect of two doses of growth hormone (GH) on final height and height velocity during the first 2 years of treatment of children with idiopathic short stature (mean baseline height standard deviation score [SDS] -3.2). STUDY DESIGN: Patients were treated with GH at 0.24 mg/kg/week, 0.24 mg/kg/week for the first year and at 0.37 mg/kg/week thereafter (0.24-->0.37), or 0.37 mg/kg/week. Final height was evaluated in 50 patients at study completion (mean treatment duration, 6.5 years). RESULTS: Patients who received 0.37 mg/kg/week (n = 72) experienced a significantly greater increase in height velocity than those who received 0.24 mg/kg/week (n = 70) (treatment difference = 0.8 cm/year; P = .003) or 0.24-->0.37 mg/kg/week (n = 67) (treatment difference = 0.9 cm/year; P = .001). For the 50 patients for whom final height measurements were available, mean height SDS increased by 1.55, 1.52, and 1.85 SDS, respectively, for the three dose groups. For the primary comparison between the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups, the mean treatment difference (adjusted for differences in baseline predicted height SDS) was 0.57 SDS (3.6 cm; P = .025). Mean overall height gains (final height minus baseline predicted height) were 7.2 cm and 5.4 cm for the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups, respectively, without dose effects on safety parameters. Final height measurements were within the normal adult height range for 94% of patients randomized to 0.37 mg/kg/week who continued to final height. CONCLUSION: GH treatment dose-dependently increases height velocity and final height in children with idiopathic short stature.