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Salti-Salem Syndrome

Slti Salem Syndrome

Salti-Salem syndrome (SSS) is a very rare entity of unknown etiology. It has only been described in a single family from Lebanon, where several members of either sex displayed hypogonadotropic hypogonadism (HH) and frontoparietal alopecia. While the condition could be attributed to decreased serum concentrations of follicle-stimulating and luteinizing hormones (FSH and LH, respectively), the genetic background has not been revealed.


Presentation

Patients present with fine, scanty hair and frontoparietal alopecia [1]. This condition may be evident from infancy, but otherwise, no abnormalities are reported before teenage years.

Adolescents suffering from SSS fail to develop secondary sexual characteristics. Male patients are typically noted to have a high-pitched voice and a eunuchoidal habitus with a decreased upper-to-lower segment ratio, long limbs, and an arm span that exceeds the height of the patient. Their external genitalia remain prepubertal, small and unpigmented. Salti and Salem described the affected boys to have an underdeveloped, short penis and small, soft testes. The prostate gland was not palpable and cryptorchidism has been noted in one of the patients. The absence of facial, axillary and pubic hair can be observed in girls and boys with SSS. Females may further report primary amenorrhea and show lack of breast development [1]. Sexual dysfunction and sterility are frequent findings in patients with HH but have not been mentioned in the original report.

None of the patients was found to have olfactory or auditory deficits.

Pallister-Hall Syndrome
  • Otofacioosseous-Gonadal Syndrome Otoonychoperoneal Syndrome otulipenia ovarian hyperstimulation syndrome Paganini-Miozzo Syndrome Pagon Stephan Syndrome Paine Syndrome Palant Cleft Palate Syndrome palindromic rheumatism Pallister Killian Syndrome Pallister W Syndrome Pallister-Hall[rgd.mcw.edu]
  • […] syndrome - See Opitz G/BBB syndrome Hypospadias-intellectual disability, Goldblatt type syndrome Hypotelorism cleft palate hypospadias Hypothalamic dysfunction Hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly - See Pallister-Hall[herenciageneticayenfermedad.blogspot.com]
Alopecia
  • Another syndrome to be mentioned in the context of co-occurring alopecia and hypogonadism is AFTS. Partial alopecia is a shared feature, although AFTS patients may also present with microcephaly, flat occiput, and mental retardation.[symptoma.com]
  • Synonyms Hypogonadotropic hypogonadism alopecia Hypogonadism and frontoparietal alopecia Overview No overview is available at this time. Please check back for future updates. For more information, visit GARD.[rarediseases.org]
  • Names and Terminology Other Names : Hypogonadotropic hypogonadism alopecia; Hypogonadism and frontoparietal alopecia ... Source: GARD (NIH) 1 ... ...[familydiagnosis.com]
  • Clinical description In addition to frontoparietal alopecia, the remaining scalp hair was also sparse, and axillary and pubic hair was absent.[orpha.net]

Workup

Besides the clinical findings described in the previous paragraph, additional signs and symptoms may corroborate the suspicion of hypogonadism, e.g., gonadotropin deficiency interferes with skeletal development and patients may display an overall delayed bone age and a reduced peak bone mass [2]. Delays in bone maturation have also been confirmed for the patients seen by Salti and Salem, although precise values regarding bone mineral content and areal bone mineral density have not been provided [1].

In general, it should be kept in mind that affected individuals may not show the entire spectrum of developmental disorders associated with hypogonadotropic hypogonadism. This is particularly true for diseases characterized by varying degrees of expressivity, as has been observed within and across families affected by idiopathic HH [3]. However, little is known about the expressivity and penetrance of mutations underlying SSS.

From a biochemical point of view, HH may be defined as low levels of sex steroids in patients with an abnormally low secretion of FSH and LH. These endocrine alterations can be confirmed by blood tests, which also allow for the distinction between hypogonadotropic and hypergonadotropic variants. The patients who were further examined by Salti and Salem, all of which were males, had decreased serum concentrations of FSH, LH, and testosterone [1]. The administration of gonadotropin-releasing hormone (GnRH) did not augment the levels of FSH and LH, which suggests gonadotropin deficiency due to pituitary dysfunction. Yet, no abnormalities were detected with regards to prolactin and growth hormone levels, the pituitary-thyroid or pituitary-adrenal axis. Serum alkaline phosphatase levels were found to be increased in two out of three patients. Beyond that, parameters of hemogram and blood chemistry were all within physiological ranges.

SSS-related alopecia is a clinical diagnosis, and the histological features of this condition have not been described in detail. A scalp biopsy has been performed in only one of the patients seen by Salti and Salem, who observed a decreased number of hair follicles [1].

Finally, the co-occurrence of early-onset frontoparietal alopecia and HH may give rise to the suspicion of SSS. Familial accumulation may suggest a hereditary disease, and genetic studies may be carried out to exclude the presence of other syndromes characterized by hypogonadism and alopecia. One of them is Woodhouse-Sakati syndrome (WSS), a rare disease that has been associated with mutations in the DCAF17 gene. DCAF17 encodes for DDB1 and CUL4-associated factor 17, a nuclear transmembrane protein [4]. Al-Awadi-Farag-Teebi syndrome (AFTS) may also be considered a differential diagnosis, but has not yet been related to a specific gene defect [5].

Treatment

All three male patients were initially administered 5000 units of human chorionic gonadotropin three times per week for 3-4 months [1]. This treatment led to a change in their habitus, rendering them more masculine and less eunochoidal. They gained weight and height and developed secondary sexual characteristics such as a deeper voice and body hair more according to age. The cryptorchid testis of one of the patients descended, and both penile and testicular growth could be observed. This development could be correlated to increasing serum concentrations of testosterone, which were now found to be within the physiological range.

The cessation of treatment with human chorionic gonadotropin resulted in a renewed decrease of gonadotropin levels. The treatment regimen was then changed to 14 months of regular therapy with human chorionic gonadotropin, which induced further masculinization, an accentuation of sexual characteristics, and further enlargement of the external genitalia [1].

It has not been described whether these men suffered from sexual dysfunction and/or infertility, and it remains unknown whether the therapeutic approach chosen by Salti and Salem may have favorably affected these conditions and promoted spermatogenesis. To date, males with HH are usually treated with long-acting testosterone esters or, if fertility is desired, with human chorionic gonadotropin plus FSH [6] [7].

Nothing has been reported about the management of SSS in affected females. In general, estrogen-progesterone replacement, calcium and vitamin D supplementation are recommended to induce normal development and growth [6]. While both gonadotropins and GnRH have been used to restore fertility in women with hypogonadotropic hypogonadism, the efficacy of the latter is questionable in SSS patients.

Prognosis

Adequate masculinization was observed in all three males treated by Salti and Salem [1]. Long-term therapy was necessary, though, since a short-term regimen resulted in testosterone levels decreasing to pretreatment values. The appearance of male secondary sexual characteristics and an increase in the size of the external genitalia were reported, without fertility being examined. Similarly, the original publication lacks information about the women's response to therapy.

It is not known whether follow-ups were conducted to ascertain whether improvements persisted and complications arose. In general, patients diagnosed with HH do experience substantial improvements of sexual, bone, metabolic, and psychological health when treated accordingly. Lifelong therapy is usually required. While the spontaneous recovery of reproductive function has been reported in some cases of congenital hypogonadotropic hypogonadism, it has not yet been described for SSS. Finally, fertility can be induced in most patients [8].

Etiology

Familial accumulation of SSS suggests a hereditary disorder, but the underlying gene defect has not been identified. In general, HH is characterized by genetic heterogeneity, with mutations in >30 genes identified to date [8]. These may either act alone or in combination, and they are further known for incomplete penetrance and variable expressivity [3]. The identification of the pattern of inheritance based on a single pedigree thus poses a major challenge. Salti and Salem assumed the disease to be inherited in an autosomal or X-linked dominant manner [1]. They speculated that the mothers of their patients, who were identical twins, may both have carried the gene defect inducing SSS. The fact that the mothers were unaffected argues against this hypothesis, but both autosomal and X-linked recessive inheritance has been ruled out: The fathers of the patients were unrelated and deemed unlikely to have carried the same mutation, and X-linked recessive diseases would rarely occur in females. Additional cases would have to be analyzed to shed more light on the genetic background of SSS.

Epidemiology

A total of six members of a Lebanese family have been described as SSS patients. Four males and two females, who were born to identical twin mothers, were affected. Consanguinity was confirmed for both families, with both mothers being married to one of their cousins. The patients presented in their late teenage years and in the early twenties, although alopecia as the first symptom of SSS has been noted from infancy in all cases [1].

Sex distribution
Age distribution

Pathophysiology

The results provided by Salti and Salem suggest SSS to be a type of secondary hypogonadotropic hypogonadism. This term refers to a disorder of the hypothalamic-pituitary-gonadal gland hormone axis that implies the inability of the pituitary gland to secrete FSH and LH upon stimulation with hypothalamic GnRH. Gonadotropin deficiency entails sex hormone deficiency and delays in the maturation and growth of reproductive organs and the development of secondary sexual characteristics. It should be noted that gonadotropins are produced in extra-pituitary tissues during early developmental stages, which explains why children suffering from pituitary gland disorders are often born with normally developed genitals [9]. Mini-puberty, however, depends on pituitary gonadotropins and may be disturbed. Cryptorchidism is one of the symptoms of impaired mini-puberty and has been observed in at least one of the patients described in the original report [1].

Prevention

Only general measures can be recommended to reduce the incidence of hereditary diseases like SSS, WSS, and AFTS. All cases mentioned in this article have been reported from areas where consanguineous marriage is favored, and all patients described by Salti and Salem were born to consanguineous parents [1]. Educational work must be realized in these regions, and people must be informed about the risks of intrafamilial reproduction [10].

Summary

In 1979, Ibrahim Salti and Zaid Salem reported a family from Lebanon harboring an unknown gene defect resulting in HH and frontoparietal alopecia. Clinical and laboratory studies revealed low serum levels of gonadotropins and normal concentrations of other pituitary hormones. The patients responded to treatment with human chorionic gonadotropin but no response could be detected to stimulation with GnRH. These observations imply secondary rather than tertiary gonadotropin deficiency, but don't allow for conclusions regarding the etiology of the condition. Autosomal dominant transmission has been named as the most likely pattern of inheritance, although X-linked dominant inheritance could not be ruled out.

SSS has later been named as a possible variant of WSS, an endocrine disorder characterized by hypogonadism and childhood-onset, progressive hair thinning [11]. WSS has been described in >30 families, mainly of Middle-Eastern origin, and may further induce diabetes mellitus, hypothyroidism, extrapyramidal movement disorders, sensorineural hearing loss, and mental retardation. Yet, none of these additional symptoms has been observed in the Lebanese family described by Salti and Salem. What's more, autosomal recessive inheritance has been proposed for WSS, while it was deemed unlikely for SSS.

Another syndrome to be mentioned in the context of co-occurring alopecia and hypogonadism is AFTS [12]. Partial alopecia is a shared feature, although AFTS patients may also present with microcephaly, flat occiput, and mental retardation. Contrary to SSS, this syndrome is associated with hypergonadotropic hypogonadism, absent or streak ovaries, and Müllerian hypoplasia [5]. AFTS was suggested to have an autosomal recessive pattern of inheritance.

Patient Information

Salti-Salem syndrome (SSS) is a very rare disease of unknown cause. It has only been described in a single family from Lebanon, where several members - both men and women - displayed hypogonadotropic hypogonadism and frontoparietal alopecia. The latter term refers to partial hair loss, and this condition may be noted from infancy. Hypogonadotropic hypogonadism is an endocrine disorder implying abnormalities of the hypothalamic-pituitary-gonadal gland hormone axis. In healthy individuals, the hypothalamus secretes gonadotropin-releasing hormone, which stimulates the pituitary gland to produce follicle-stimulating and luteinizing hormones, which act on the gonads, which produce sex hormones. Any condition interfering with the release of follicle-stimulating and luteinizing hormones by the pituitary gland thus results in sex hormone deficiency. This is most easily observed in teenage years, because affected individuals don't develop secondary sexual characteristics such as breast development and the onset of menstrual bleeding in females, beard growth in males, and the appearance of axillary and pubic hair in either sex. Both boys and girls change body proportions and their genitals develop and increase in size. These changes don't occur in SSS patients with absent puberty.

SSS is assumed to be a hereditary disorder, although the underlying gene defect could not yet be identified. Accordingly, there is no causal treatment, but patients generally respond well to hormone replacement therapy and show improvements of sexual, bone, metabolic, and psychological health.

References

Article

  1. Salti IS, Salem Z. Familial hypogonadotropic hypogonadism with alopecia. Can Med Assoc J. 1979; 121(4):428-430, 433-424.
  2. Laitinen EM, Hero M, Vaaralahti K, Tommiska J, Raivio T. Bone mineral density, body composition and bone turnover in patients with congenital hypogonadotropic hypogonadism. Int J Androl. 2012; 35(4):534-540.
  3. Pitteloud N, Durrani S, Raivio T, Sykiotis GP. Complex genetics in idiopathic hypogonadotropic hypogonadism. Front Horm Res. 2010; 39:142-153.
  4. Alazami AM, Al-Saif A, Al-Semari A, et al. Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet. 2008; 83(6):684-691.
  5. Al-Obaidi RGY, Al-Musawi BMS. Primary hypogonadism, partial alopecia, and Mullerian hypoplasia: report of a fifth family and review. Clin Case Rep. 2017; 5(10):1634-1638.
  6. Silveira LF, Latronico AC. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013; 98(5):1781-1788.
  7. Zacharin M, Sabin MA, Nair VV, Dabadghao P. Addition of recombinant follicle-stimulating hormone to human chorionic gonadotropin treatment in adolescents and young adults with hypogonadotropic hypogonadism promotes normal testicular growth and may promote early spermatogenesis. Fertil Steril. 2012; 98:836-842.
  8. Young J, Xu C, Papadakis GE, et al. Clinical Management of Congenital Hypogonadotropic Hypogonadism. Endocr Rev. 2019; 40(2):669-710.
  9. Kumar PA, Pitteloud N, Andrews PA, et al. Testis morphology in patients with idiopathic hypogonadotropic hypogonadism. Hum Reprod. 2006; 21(4):1033-1040.
  10. Barbour B, Salameh P. Consanguinity in Lebanon: prevalence, distribution and determinants. J Biosoc Sci. 2009; 41(4):505-517.
  11. Bohlega SA, Alkuraya FS. Woodhouse-Sakati Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
  12. Al-Awadi SA, Farag TI, Teebi AS, et al. Primary hypogonadism and partial alopecia in three sibs with mullerian hypoplasia in the affected females. Am J Med Genet. 1985; 22(3):619-622.

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Last updated: 2019-07-11 21:20