1) When thyroid hormone production was reduced by PTU, high doses of LT(4) (3.7 microg/kg.d) were needed to normalize serum TSH, confirming that mutation of MCT8 is a cause of resistance to thyroid hormone. 2) High T(3) levels might exhibit some deleterious effects on adipose, hepatic, and cardiac levels. 3) PTU plus LT(4) could be an effective therapy to reduce general adverse features, unfortunately without benefit on the psychomotor retardation.

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Objective: Hypothyroidism is a manifestation of multi-hormonal resistance in pseudohypoparathyroidism type Ia (PHP Ia). The objective of the study was to determine the mechanisms of hypothyroidism in PHP Ia. Design: A prospective study. Patients: Ten patients with PHP Ia. Measurements: The serum concentrations of TSH, free triiodothyronine (FT 3 ), free thyroxine (FT 4 ), and prolactin (PRL) were measured at baseline and after stimulation with TRH (200 mg i.v). Results: The median basal serum TSH concentration was 4.92 mU/l. Basal serum TSH concentration was slightly elevated in eight patients (4.22-7.0 mU/l; normal range, 0.4-3.6 mU/l), normal in one patient (2.5 mU/l), and high in one patient (13.1 mU/l). After the TRH test, TSH concentrations increased to 13.4-36.0 mU/l (normal range, 4.0-20.0 mU/l). The absolute values after the test were normal in three patients and high in seven patients. However, TSH responses relative to the baseline value (stimulated/basal TSH and expressed as a fold increase), which reflect the relative increases after TRH stimulation, were low in seven patients (2.3-to 4.3-fold TSH) and normal in three patients. Basal FT 4 concentration was normal in seven patients and low in three patients (range, 8.4-20.0 pmol/l; mean, 14.1G4.3 pmol/l; normal range, 10.5-23.0 pmol/l). Basal FT 3 concentration was normal in nine patients and low in one patient (range, 0.9-5.0 pmol/l; mean, 3.8G1.1 pmol/l; normal range, 3.3-6.1 pmol/l). FT 4 and FT 3 were not significantly increased after the TRH test. PRL concentration was normal at baseline and increased from 7 to 96 ng/ml after TRH. Conclusion: Our results support the hypothesis that patients with PHP Ia have impaired sensitivity to both TSH and TRH.

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Objective The term Multiple Symmetric Lipomatosis (MSL) describes a heterogeneous group of rare monogenic disorders and multifactorial conditions, characterized by upper-body adipose masses. Biallelic variants in LIPE encoding hormone sensitive lipase (HSL), a key lipolytic enzyme, were implicated in three families worldwide. We aimed to further delineate LIPE-related clinical features and pathophysiological determinants. Methods A gene panel was used to identify pathogenic variants. The disease features were reviewed at the French lipodystrophy reference center. The immunohistological, ultrastructural, and protein expression characteristics of lipomatous tissue were determined in surgical samples from one patient. The functional impact of variants was investigated by developing a model of adipose stem cells (ASCs) isolated from lipomatous tissue. Results We identified new biallelic LIPE null variants in three unrelated patients referred for MSL and/or partial lipodystrophy. The hallmarks of the disease, appearing in adulthood, included lower-limb lipoatrophy, upper-body and abdominal pseudolipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Ophthalmological investigations revealed numerous auto-fluorescent drusen-like retinal deposits in all patients. Lipomatous tissue and patient ASCs showed loss of HSL and decreased expression of adipogenic and mature adipocyte markers. LIPE-mutated ASCs displayed impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction. Conclusions Biallelic LIPE null variants result in a multisystemic disease requiring multidisciplinary care. Loss of HSL expression impairs adipocyte differentiation, consistent with the lipodystrophy/MSL phenotype and associated metabolic complications. Detailed ophthalmological examination could reveal retinal damage, further pointing to the nervous tissue as an important disease target.

In patients with pseudohypoparathyroidism, hormonal resistance first affects parathyroid hormone (PTH), which leads to calcipenia, a decrease in renal vitamin D activation, and a tendency to bone receptor remodeling. However, because G proteins are ubiquitously distributed, multiple hormonal resistance occurs in pseudohypoparathyroidism type Ia and type Ic, impairing responses to other calciotropic hormones (PTHrP, calcitonin), TSH, and also pituitary and hypothalamic hormones, and to neurosensory stimuli. The diversity of multihormonal resistance contributes to the various phenotypes of the disease. Some clinical discomfort and medical consequences of the disease can be treated or prevented with hormone supplementation or modulation.

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