An Atypical Case of Head Tremor and Extensive White Matter in an Adult Female Caused by 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase deficiency (HMGLD) (OMIM 246450) is an autosomal recessive genetic disorder caused by homozygous or compound heterozygous variants in the HMGCL gene located on 1p36.11. Clinically, this disorder is characterized by a life-threatening metabolic intoxication with a presentation including severe hypoglycemia without ketosis, metabolic acidosis, hyper-ammoniemia, hepatomegaly and a coma. HMGLD clinical onset is within the first few months of life after a symptomatic free period. In nonacute periods, the treatment is based on a protein- and fat-restricted diet. L-carnitine supplementation is recommended. A late onset presentation has been described in very few cases, and only two adult cases have been reported. The present work aims to describe an incidental discovery of an HMGLD case in a 54-year-old patient and reports a comprehensive review of clinical and biological features in adult patients to raise awareness about the late-onset presentation of this disease.

A single-amino-acid in-frame deletion in CYP17A1 results in combined 17-hydroxylase and 17,20-lyase deficiency in an Iranian family despite the protein mutation site

In this study, we detected homozygous mutations in the CYP17A1 gene (NM_000102.4:c.1053_1055delCCT; p.Leu353del; SCV001479329) in a 28-year-old female patient (46,XX) and her phenotypically female 30-year-old sister (46,XY) who had phenotypes consistent with combined 17-hydroxylase and 17,20-lyase deficiency. The phenotypes were not expected based on the location of the mutation in the CYP17A1 redox partner-binding site and a previous description of the same mutation linked with isolated 17,20-lyase deficiency.

Successful delivery in 17,20-lyase Deficiency

Objective To study and describe the achievement of successful pregnancy and delivery in a patient with 17,20-lyase deficiency. Design Controlled ovarian stimulation (COS) and In Vitro fertilization (IVF), cryopreservation of embryos and frozen-thawed embryo transfer (ET). Setting IVF clinic. Patient A 24 years old, infertile patient with 17,20-lase deficiency. Interventions Controlled ovarian stimulation, follicular aspiration- egg retrieval, IVF, embryo cryopreservation, thawed ET. Main Outcome Measures Clinical pregnancy, successful delivery. Results Isolated 17,20-lyase deficiency is caused by mutations in the CYP17A1 gene (coding for cytochrome P450c17), POR (coding for cytochrome P450 oxidoreductase) and CYB5A (coding for microsomal cytochrome b5) genes. A 24 yo patient with 17,20-lyase deficiency had undergone IVF with gonadotropin releasing hormone agonist (GnRHa) protocol, prednisone, and gonadotropins. After human chorionic gonadotropin (hCG) trigger 37 oocytes were retrieved, 25 ova fertilized, and 17 embryos cryopreserved. After menstrual bleeding, the endometrium was stimulated with oral estradiol, under progesterone suppression with long acting GnRHa and prednisone. When endometrial width of 8.5 mm was reached, vaginal progesterone was added, while gradually decreasing prednisone. On the fourth day of progesterone supplement, two thawed embryos were transferred. After 11 days of human menopausal gonadotropin (hMG), estradiol concentration moderately increased, but progesterone levels remained high, therefore, no fresh ET was performed. Twelve days after thawed ET, hCG was positive, and seven days later, an intrauterine gestational sac was detected, but the pregnancy ended in missed abortion. After two months, another frozen-thawed embryo transfer (FET) was performed, generating a normal gestation, which ended in successful delivery. Conclusion Pregnancy can be achieved in patients with 17,20-lyase deficiency, by IVF, freezing all embrya, and ET in a subsequent cycle, while suppressing endogenous ovarian progesterone with a GnRHa and adrenal suppression with high dose glucocorticoids.

Genotypic Sex and Severity of the Disease Determine the Time of Clinical Presentation in Steroid 17α-Hydroxylase/17,20-Lyase Deficiency

<b><i>Context:</i></b> Steroid 17α-hydroxylase/17,20-lyase deficiency (17OHD) is characterized by decreased sex steroids and cortisol, and excessive mineralocorticoid action. The clinical symptoms of hypocortisolemia are subtle. <b><i>Aim:</i></b> The clinical, biochemical, and molecular characteristics of patients with 17OHD were evaluated to determine the factors influencing the time of diagnosis and the management. <b><i>Patients and Methods:</i></b> Clinical data, steroid profiles by liquid chromatography-tandem mass spectrometry, and Sanger sequencing of the <i>CYP17A1</i> gene was evaluated in 12 patients with 17OHD diagnosed between 2004 and 2020. <b><i>Results:</i></b> Median age of diagnosis was 13.9 (range: 0.04–29.5) years. Ten of 12 patients had 46,XY karyotype. Except for one boy with partial 17OHD, all patients had female external genitalia hence raised as females. The clinical presentation of 17OHD was earlier (median age: 7 years) in patients, who presented with severe hypertension, atypical genitalia, or positive family history (<i>n</i> = 6, 50%) than those without (median age: 15.3 years; <i>p</i> = 0.0005). The latter group presented with amenorrhea (<i>n</i> = 6, 50%). Steroid profile of patients uniformly showed a typical pattern of 17OHD regardless of the age at diagnosis. Serum gonadotropin concentrations were elevated in patients &#x3e;12 years (<i>n</i> = 7), normal in pre-adolescents (<i>n</i> = 4), and low in a patient, who had a digenic inheritance of homozygous <i>CYP17A1</i> and <i>KISS1R</i> mutations. <b><i>Conclusions:</i></b> Early clinical presentation and diagnosis in 17OHD are associated with symptomatic hypertension in both 46,XX and 46,XY patients or inadequate virilization of external genitalia in 46,XY partial 17OHD. In the absence of these, the clinical presentation is at late pubertal ages at which time amenorrhea and elevated gonadotropins are the hints for diagnosis.