Context: Spinal muscular atrophy (SMA) is an autosomal recessive inherited disease characterized by degeneration of anterior horn cells of the spinal cord and brainstem resulting in variable degrees of muscular atrophy and proximal muscle weakness. In December 2016, nusinersen was FDA-approved for the treatment of SMA in pediatric and adult patients. The introduction of this therapeutic modality has provided a platform for professional medical-care providers in our national neuromuscular center. To the best of our knowledge, this is the first report on endocrine manifestations in patients with severe forms of SMA.
Aims: To identify endocrine characteristics of SMA patients with precocious pubarche.
Methods: Real-life data in 62 SMA patients (24 type 1, 21 type 2, 17 type 3) were collected during routine clinic visits prior to nusinersen intervention. Anthropometric measurements and pubertal stage were determined by pediatric endocrinologists. Self-reported onset of puberty was documented for patients in puberty/fully pubertal. Laboratory evaluation included kidney and liver function tests, measures of glucose metabolism (fasting blood glucose and insulin levels, calculation of Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]), basal androgen profile levels (testosterone,17-hydroxyprogesterone, androstenedione and dehydroepiandrosterone sulfate) and as clinically indicated - Synacthen stimulation testing for the diagnosis of adrenal enzymatic disorders.
Results: Twenty-four percent (15/62) of the studied cohort had precocious pubarche, 45.9% (11/24) with SMA type 1, and 19% (4/21) with SMA type 2. One of the type 2 patients with rapid progression of adrenarche was diagnosed with non-classic congenital adrenal hyperplasia by Synacthen test and was excluded from analysis. Fourteen patients with precocious pubarche (mean age at onset 3.9 ± 2.8 years), without rapid progression had no other clinical signs or laboratory evidence of hyperandrogenism. SMA patients with precocious pubarche were characterized by significantly higher HOMA-IR levels (4.1 ± 2.9 vs. 2.4 ± 1.9, P < 0.001) and significantly lower creatinine levels (0.09 ± 0.04 vs. 0.20 ± 0.12, P = 0.001) compared to those without precocious pubarche. Body mass index SDS / weight-for-length SDS of the study cohort was relatively low (-1.34 ± 2.65), with no significant differences between groups.
Conclusions: Our findings suggest that isolated precocious pubarche is a common clinical manifestation in the severe types of SMA with markedly decreased muscle mass. Isolated precocious pubarche in those patients is characterized by increased insulin resistance without laboratory evidence of hyperandrogenism. Further studies are warranted to delineate the role of sarcopenia and body fat/muscle imbalance in extreme underweight patients with precocious pubarche.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology