Cholesterol is essential to human life. Perturbations to any of the 22 cholesterol synthesis enzymes can lead to devastating developmental diseases. Each enzyme is exquisitely regulated both transcriptionally and post-translationally, playing a critical role in providing cholesterol to cells. We examined 13 missense mutations and one deletion mutation in the cholesterol synthesis enzyme NSDHL (NAD(P) Dependent Steroid Dehydrogenase-Like), known to cause the X-linked developmental disorders CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome and CK syndrome. Little is known about the effect of these missense mutations on the stability and function of NSDHL. Here we show that protein expression levels were low for all mutants, but some could be rescued by a lower temperature (30°C vs. 37°C) and/or the chemical chaperone glycerol. Additionally, heat shock proteins 70 and 90 are needed for optimal NSDHL protein expression suggesting that disease mutations in NSDHL may interfere with this interaction, perhaps during translation resulting in lower protein synthesis. Our findings that these disease-causing mutations reduce NSDHL protein expression, but some respond to lower temperature and/or the chemical chaperone glycerol, can help inform future treatments for CHILD and CK syndrome. NSDHL-related disorders include CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked disorder that is usually male lethal during gestation and thus predominantly affects females; and CK syndrome, an X-linked disorder that affects males. CHILD syndrome is characterized by unilateral distribution of ichthyosiform skin lesions and ipsilateral limb defects that range from shortening of the metacarpals and phalanges to absence of the entire limb. Intellect is usually normal. The ichthyosiform skin lesions are usually present at birth or in the first weeks of life; new lesions can develop in later life. Onychodystrophy and periungual hyperkeratosis are common. Heart, lung, and kidney malformations can also occur. CK syndrome is characterized by mild-to-severe cognitive impairment and behavior problems (aggression, attention-deficit/hyperactivity disorder [ADHD], and irritability). All reported affected males have developed seizures in infancy and have cerebral cortical malformations and microcephaly. All have distinctive facial features, a thin habitus, and relatively long, thin fingers and toes. Some have scoliosis and kyphosis. Strabismus is common. Optic atrophy is also reported. The diagnosis of CHILD syndrome is established in a female proband with a heterozygous NSDHL pathogenic variant identified by molecular genetic testing that results in loss of functional decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase, the protein encoded by NSDHL. The diagnosis of CK syndrome is established in a male proband with a hemizygous NSDHL hypomorphic pathogenic variant identified by molecular genetic testing that results in partial loss of functional decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase. Treatment of manifestations: In CHILD syndrome, no one therapy described to date appears to ameliorate the cutaneous findings for every reported individual. Oral and topical ketoconazole may reduce lesions. Topical statin treatment alone or combined with cholesterol and/or glycolic acid can be beneficial. Treatment of an inflammatory nevus by grafting skin obtained from a contralateral unaffected region has been successful. Lactic acid 12% creams or lotions can reduce itching, and urea skin creams can reduce dryness. Scoliosis and joint contractures are treated with braces and/or corrective surgery. Standard management for heart, lung, kidney, and gastrointestinal manifestations. In CK syndrome, developmental and educational support; behavior modification and/or drug therapy to control aggression and help with manifestations of ADHD; anti-seizure medication to control seizures; standard treatments for orthopedic and ocular manifestations; support transition to adult care; and social work and family support as needed. Surveillance: In CHILD syndrome, monitor for new cutaneous lesions, musculoskeletal deformities such as scoliosis and joint contractures, and neurologic, cardiac, and/or kidney manifestations annually or as needed. In CK syndrome, monitor for developmental and educational progress, behavioral issues, changes in seizures, and development of scoliosis and/or kyphosis annually or as needed. Follow-up ophthalmology examination per ophthalmologist. NSDHL-related disorders are inherited in an X-linked manner. CHILD syndrome is usually male lethal during gestation and thus predominantly affects females. CK syndrome predominantly affects males. CHILD syndrome: If the mother of a proband has an NSDHL pathogenic variant, the chance of transmitting it in each pregnancy is 50%. However, since studies suggest that male conceptuses with an NSDHL pathogenic variant generally abort or resorb spontaneously, the expected live-born distribution is: 33% heterozygous (typically) affected females; 33% unaffected females; and 33% unaffected males. CK syndrome: If the mother of a proband is heterozygous for an NSDHL pathogenic variant, the expected chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and may have a range of behavioral problems. Identification of female heterozygotes requires prior identification of the NSDHL pathogenic variant in the family. Once the NSDHL pathogenic variant has been identified in a family member with an NSDHL-related disorder, prenatal and preimplantation genetic testing are possible.

A 67-year-old male had prostate adenocarcinoma with liver, bone metastases, iliac lymph nodes invasion ever receive hormone and chemotherapy. He was presented to our emergency department with acute onset of mild dizziness and shortness of breath. Elevated CK (1477 U/L) and elevated CK-MB (1602 U/L) was noticed. Electrocardiogram was unremarkable for myocardial ischemia. CK-isoenzyme lab test (electrophoresis) was obtained, which revealed macro CK type 2 accounting for 6.2% of total CK. Type 2 macro CK syndrome was impressed. The falsely elevated CK-MB and macro CK type 2 in serum may be associated with the patient's worsening metastatic disease.

CK syndrome is a rare disorder caused by mutation in the NSDHL (NAD(P) dependent steroid dehydrogenase-like) gene at the Xq28 locus. It has expanded the spectrum of disorders associated with X-linked mental retardation and defects in sterol metabolism. There are only a few reports defining the phenotypic spectrum of this rare disorder. We describe a new patient from the Indian subcontinent who presented with dysmorphism, global developmental delay and epilepsy. We also add left ventricular concentric hypertrophy and sensory neuropathy, which have not been reported previously. Our report suggests that CK syndrome may be unrecognized due to limited clinical knowledge and restricted availability of genetic testing. The expansion of the phenotype may also lead to a better understanding of biochemical anomalies and management approaches.

To refine the spectrum of anti-Ku-associated disease, a condition that is equivocally described by current diagnostic criteria for connective tissue diseases. Among 42 consecutive patients harbouring anti-Ku antibodies, subgroups with similar phenotypes and prognosis were delineated without an a priori diagnosis using hierarchical clustering analysis of the cumulative clinico-biological features recorded during the follow-up. Features present at baseline that most efficiently predicted the outcomes were then identified using a sensitivity-specificity sum maximisation approach. Clinico-biological features were clustered into three groups. Glomerulonephritis and ILD, the two fatal complications in this cohort, were unequally distributed between the three clusters that additionally differed on six clinico-biological features.Among features present at baseline, elevated serum level of creatine kinase (CK) and anti-dsDNA antibodies were generally mutually exclusive and most efficiently predicted the cluster belonging at last follow-up. Anti-Ku patients with elevated CK had a 22-fold higher risk of ILD while anti-Ku patients with anti-dsDNA antibodies had a 13-fold higher risk of glomerulonephritis CONCLUSION: "Anti-Ku with elevated CK" syndrome and "anti-Ku with anti-dsDNA" syndrome represent two distinct entities that are important to recognise in order to best tailor patient care.