Bose et al. (1996) sequenced the STAR gene in an Egyptian patient with congenital lipoid adrenal hyperplasia of Coptic Christian heritage; and, hence, probably a member of a different gene pool. This patient resulted from a consanguineous marriage and her karyotype was XY. She was homozygous for the frame shift mutation in exon 4 of the STAR gene (548/InsTT/549). The mutation was confirmed and recreated in expression vectors, transfected into cultured cells, and assayed for the presence and activity of steroidogenic acute regulatory protein.

[See: Palestine > Bose et al., 1996]

[Gucev et al. (2013) described two siblings (46,XX and 46,XY) who presented in the first month of their lives with severe glucocorticoid and mineralocorticoid deficiency and with a normal female external genitalia. There was no evidence of adrenal hyperplasia on abdominal US, prompting a diagnosis of P450scc deficiency. Sequencing of the STAR gene identified a homozygous novel 14-bp deletion/frameshift mutation in exon 4, confirming the diagnosis of Lipoid Congenital Adrenal Hyperplasia. The mutation was found in a heterozygous state in both parents as well as an unaffected sibling.

[See also: Palestine > Bose et al., 1996].

In a consanguineous family from Libya, Achermann et al. (2001) identified a novel homozygous T to G transversion within the splice donor site of exon 1 of the STAR gene (IVS1+2T>G, g.66) in two sisters (46XY, 46XX) affected with LCAH.

Bose et al. (1996) sequenced the STAR gene either directly (exons 1 through 4) or manually (exons 5 through 7) in six patients with congenital lipoid adrenal hyperplasia of Palestinian ancestry. Their karyotypes were XY, except one with the XX karyotype. Two patients were siblings, including the one with the XX karyotype, and one patient was from a consanguineous marriage. These six patients represented nine unique alleles, seven of which (78%) were found to have the Arg182Leu mutation (G671T in exon 5). These apparently unrelated patients were from Jordan, Kuwait, Palestine, and Denmark. This mutation was found with other mutations in two patients: the frame shift mutations (delta2T593, and deltaC650, both in exon 5). Identification of intronic polymorphisms and other mutations within the STAR gene showed that the Arg182Leu mutation was found in various sequence contexts, confirming that the patients were unrelated. The patient from consanguineous parents was found to be homozygous for the Glu169Gly mutation (A632G in exon 5). Identified mutations were confirmed and recreated in expression vectors, transfected into cultured cells, and assayed for the presence and activity of steroidogenic acute regulatory protein. By performing DNA sequencing of the STAR gene, Bose et al. (2000) identified a novel mutation T for C at nucleotide 703 in exon 5 of the STAR gene, resulting in the premature stop codon R193X. The patient, with an XX karyotype, had the mutation in homozygous form. She was a Palestinian female with lipoid congenital adrenal hyperplasia. She was the third surviving child of a consanguineous marriage with twin premature girls, a term male who died in infancy, and two spontaneous abortions.

By performing direct DNA sequencing for all seven exons of the STAR gene, Bhangoo et al. (2005) identified a novel dinucleotide deletion (327_328delCT) in exon 3 of the STAR gene that induces a frame shift that truncates the StAR protein after 68 amino acids and eliminates key functional domains of the StAR protein. This mutation was identified in two sisters affected with lipoid congenital adrenal hyperplasia and born to healthy consanguineous parents of Palestinian descent. These two XX siblings presented with neonatal adrenal insufficiency. One had a borderline intelligence quotient and features of attention deficit hyperactivity disorder. MRI showed areas of supratentorial white matter lesions. In her sister, MRI revealed a Chiari-I malformation. The parents and three other sisters were neurologically normal and were found to be heterozygous for this mutation. Bhangoo et al. (2005) concluded that these cases from Palestine as well as Yemen reported in their study broaden the spectrum of known StAR mutations and suggest that disorders of central nervous system development may arise because of StAR deficiency and/or the metabolic consequences of neonatal adrenal deficiency [See: Yemen > Bhangoo et al., 2005].

Abdulhadi-Atwan et al. (2007) studied eight Palestinians from four unrelated families with congenital lipoid adrenal hyperplasia. All affected individuals (3 XY, 5 XX) presented neonatally with undetectable adrenocortical hormones and are responding to replacement therapy. Only two sisters, originally reported by Bhangoo et al. (2005), had neurodevelopmental deficits. Histopathologic findings of excised XY gonads included accumulation of fat in Leydig cells. As early as 1 year of age, positive placental alkaline phosphatase and octamer binding transcription factor staining indicated neoplastic potential. Sequence analysis of STAR revealed homozygosity for a 2-bp deletion (201_202delCT) in all eight cases, causing premature termination at amino acid 68 of the STAR protein. All of the parents were carriers of the mutation, which was confirmed to be a founder mutation. The mutation was not found in 100 normal Palestinians from Jerusalem. Abdulhadi-Atwan et al. (2007) noted that Bhangoo et al. (2005) had reported this mutation in the two sisters as 327_328delCT based on a different numbering system.

In a family from Qatar, Achermann et al. (2001) identified a novel homozygous R182H missense mutation in the putative lipid transfer domain of StAR in a phenotypic female (46XY) with adrenal failure and a parotid tumor. This mutation was confirmed by MaeIII digestion. Immunohistology of the testis showed low-level StAR expression in the uncanalated seminiferous tubules, but there was no evidence of StAR expression in the interstitium. No StAR expression was also detected in the parotid tumor in this patient by immunohistochemistry or in normal human or mouse parotid by RT-PCR.

By sequencing all coding regions of the StAR gene, Chen et al. (2005) detected two mutations in eight patients with lipoid CAH from six families of native Saudi Arabian descent. Five families are from the eastern (Ash-Sharqiyah) province, whereas one family originates from a different part of Saudi Arabia (the northern or AlHudud Ash-Shamaliyah Province). Consanguinity was present in four families and intermarriage occurred between two of these families. Five patients were 46,XY and three were 46,XX. The patient from northern Saudi Arabia was found to be homozygous for the M144R missense mutation (T to G at position 431); both parents were found to be heterozygous for the same mutation. The other seven patients were all homozygous for the R182H missense mutation (G to A at base position 545). All available parental samples were found to heterozygous for the same mutation. Each mutation was recreated in a human StAR cDNA expression vector and found to be wholly inactive in a standard assay of COS-1 cells cotransfected with the cholesterol side-chain cleavage enzyme system. The age of onset of symptoms among the seven patients with the R182H mutation ranged from 1 month to 14 months, however, onset of clinical symptoms and laboratory evidence of salt loss were noted at 3 weeks of age in a patient from Qatar with the same R182H mutation [See: Qatar > Achermann et al., 2001]. This finding led Chen et al. (2005) to speculate on the presence of a dramatic spectrum of clinical presentations in the same ethnic group with the same mutation. Also, the high incidence of R182H led Chen et al. (2005) to suggest that physicians caring for patients from the eastern Arabian Peninsula should consider this mutation in the diagnosis of the sick infants and may wish to consider its prenatal diagnosis in appropriately selected families.

Bhangoo et al. (2005) identified a novel missense mutation (R182C) in exon 5 of the STAR gene, by performing direct DNA sequencing for all seven exons of the gene. This mutation was found in homozygous state in an XY subject with lipoid congenital adrenal hyperplasia of consanguineous parents of Yemeni descent presented with adrenal insufficiency and severe undervirilization. Magnetic resonance imaging (MRI) of the brain showed enlarged subarachnoid spaces consistent with frontal and temporal atrophy. The neurologically normal parents were found to be heterozygous for this mutation. The steroidogenic factor-1 (SF-1) gene was also analyzed and its DNA sequence was normal [See: Palestine > Bhangoo et al., 2005].