Alternative titles; symbols
ORPHA: 2273, 85284; DO: 0111821;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.12 | IFAP syndrome with or without BRESHECK syndrome | 308205 | X-linked recessive | 3 | MBTPS2 | 300294 |
A number sign (#) is used with this entry because of evidence that IFAP syndrome-1 with or without BRESHECK syndrome (IFAP1) is caused by mutation in the MBTPS2 (300294) gene on chromosome Xp22.
See also X-linked keratosis follicularis spinosa (KFSDX; 308800), an allelic disorder with an overlapping phenotype.
The IFAP/BRESHECK syndrome is an X-linked multiple congenital anomaly disorder with variable severity. The classic triad, which defines IFAP, is ichthyosis follicularis, atrichia, and photophobia. Some patients have additional features, including mental retardation, brain anomalies, Hirschsprung disease, corneal opacifications, kidney dysplasia, cryptorchidism, cleft palate, and skeletal malformations, particularly of the vertebrae, which constitutes BRESHECK syndrome (summary by Naiki et al., 2012).
Genetic Heterogeneity of IFAP Syndrome
IFAP syndrome-2 (IFAP2; 619016) is caused by heterozygous mutation in the SREBF1 gene (184756) on chromosome 17p11.
Early Reports
The syndrome of ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) was first described by MacLeod (1909), who reported a family in which 3 of 5 boys were affected. He was struck by the peculiar association of severe follicular hyperkeratosis presenting on the scalp, the extensor surfaces of the limbs, and the abdomen, with complete baldness. The boys had been referred to him because they suffered from 'trachoma.' MacLeod (1909) pointed out that in addition to the follicular lesions the skin was 'dry and harsh from the presence of fine scaliness.' 'Trachoma,' probably consequent to vascularizing keratitis, was noted in the patients at birth or soon thereafter, while onset of the keratotic lesions was not before the age of 2 and the baldness developed from 7 years on.
The disorder fell into oblivion until Zeligman and Fleisher (1959) observed 2 boys with follicular ichthyosis, alopecia, and photophobia. Eramo et al. (1985) described 2 more boys with this unique triad of abnormalities: ichthyosis follicularis with alopecia and photophobia.
Broadened Descriptions and Definitions
Martino et al. (1992) described the case of a boy with features of the IFAP syndrome and of another presumably X-linked recessive ectodermal dysplasia, dermotrichic syndrome, described by Freire-Maia and Pinheiro (1984). The 2 syndromes share generalized ichthyosiform lesions and atrichia from birth, associated with short stature, mental retardation, and seizures. The 2 syndromes can be differentiated mainly on the basis of skeletal and intestinal anomalies present in the dermotrichic syndrome and ocular and respiratory disorders in the IFAP syndrome. In the patient reported by Martino et al. (1992), most manifestations of the 2 syndromes were present as well as additional ones. He had short stature, mental retardation, seizures, follicular ichthyosis, generalized alopecia, hypohidrosis, enamel dysplasia, photophobia, congenital aganglionic megacolon, inguinal hernia, and vertebral and renal anomalies. The chromosome constitution was normal. Photophobia and recurrent respiratory infections are characteristic of the IFAP syndrome; nail anomalies, hypohidrosis, megacolon, and vertebral defects are characteristic of dermotrichic syndrome. Enamel dysplasia, renal anomalies, and inguinal hernia are additional features. Two maternal uncles had had alopecia and ichthyosis. Various possibilities were suggested, including pleiotropism of a single gene resulting in the 2 disorders and a contiguous gene syndrome. Naiki et al. (2012) commented that the patient reported by Martino et al. (1992) had clinical features similar to those of BRESHECK syndrome (Reish et al., 1997).
Reish et al. (1997) used the acronym BRESEK to denote the common findings, and BRESHECK for all manifestations, found in 2 maternally related half brothers with multiple congenital anomalies: brain anomalies, retardation, ectodermal dysplasia, skeletal deformities, Hirschsprung disease, ear/eye anomalies, cleft palate/cryptorchidism, and kidney dysplasia/hypoplasia. The first half brother was born at 32 weeks' gestation after a pregnancy complicated by intrauterine growth retardation and oligohydramnios. Multiple congenital anomalies were noted, including acrocephaly, right microphthalmia, lamellar desquamation and generalized alopecia of the scalp/eyebrows/eyelashes, scoliosis and hypoplasia of the right chest, bilateral talipes calcaneus, unilateral postaxial polydactyly, and multiple flexion contractures with a dislocated hip. He died of respiratory distress 6 hours after delivery. An autopsy revealed enlarged lateral cerebral ventricles, absence of the septum pellucidum, fusion of the thalami, dilation of the central thoracic spinal cord, hypoplastic lungs, dysplastic and multicystic kidneys without ureters, a hypoplastic bladder with no external orifice, and 1 umbilical artery. Microscopy showed epidermal changes consistent with a form of ectodermal dysplasia. Rectal sections demonstrated normal ganglion cells. Cytogenetic studies were normal. The second half brother was born at term with IUGR and multiple anomalies, including asymmetric head with plagiocephaly and flattening of right occiput, submucous clefting, small and oval-shaped optic nerves, generalized alopecia, and dry and scaly skin with hyperkeratotic lesions. He developed complex neonatal seizures, and an MRI showed thinning of the corpus callosum with dilatation of the ventricles. Brainstem evoked response testing revealed a mixed hearing loss, and survey showed several rib and vertebral anomalies. Renal studies showed agenesis of the left kidney with a small bladder and severe reflux on the right. Plasma amino acids, urine organic acids and reducing substances, and cytogenetic studies were normal. At 5 weeks of age, the child developed intestinal obstruction and was diagnosed with Hirschsprung disease. Reexamination at 7 years of age demonstrated marked developmental and somatic growth delay. Family history was remarkable for the mother having a brother who died a few hours after delivery of undefined cause but with a reported failure of growth, further suggesting an X-linked disorder.
Keyvani et al. (1998) described the clinical and autopsy findings in a sporadic case of IFAP syndrome. The patient was born of a 40-year-old father and a 33-year-old mother. During early infancy, congenital ichthyosis and alopecia, but apparently normal development, were present. Photophobia and generalized myoclonic-astatic seizures began during or after the first year of life and were associated with progressive impairment of motor skills and mental abilities. The patient died at 33 years of age. Neuropathologic findings showed an unusual deformation of the temporal lobes and olivocerebellar atrophy.
Boente et al. (2000) reported a boy with a severe form of IFAP syndrome who had total alopecia and dry skin at birth. He presented at age 3.5 years for evaluation of mental and growth retardation and seizures. Physical examination showed weight, length, and head circumference below the third percentile. He had no scalp or body hair, and absent eyebrows and eyelashes. There was a generalized lamellar desquamation, with slight underlying erythema. Thicker and darker scales were present over the scalp, knees, wrist, and ankles. Follicular hyperkeratosis and mild keratoderma on the palmar and plantar surfaces were present. The nails were dystrophic, with onychia and paronychia due to candida. Teeth and sweating were normal. Ophthalmologic examination disclosed marked photophobia, and slit-lamp examination showed a vascularizing keratitis. Neurologic examination revealed severe mental retardation, and MRI showed hyperintense signals in the brainstem. Skin biopsies showed focal parakeratosis, loss of hair follicles, and no sebaceous glands. A large inguinal hernia, a feature in the patient reported by Martino et al. (1992), was also present. Family history revealed that the mother's first cousin had a son with a similar condition. Differentiation from the keratitis-ichthyosis-deafness syndrome (148210) was discussed.
Megarbane et al. (2004) described 2 brothers with ichthyosis follicularis, noncicatricial universal alopecia, photophobia, hyperkeratotic psoriasis-like lesions, dystrophic nails, inguinal hernias, cryptorchidism, short stature, seizures, and psychomotor developmental delay. The younger brother also had bilateral absent fourth fingers and camptodactyly, which the authors stated had not previously been described in IFAP.
Naiki et al. (2012) reported a Japanese boy with multiple severe congenital anomalies consistent with BRESHECK syndrome. At birth, he was noted to have generalized alopecia, and he lacked eyelashes, scalp hair, and eyebrows. The skin on the entire body was erythematous with continuous desquamation. He developed seizures at age 5 months, showed abnormal auditory brainstem responses at age 8 months, developed photophobia, and showed delayed psychomotor development. He was also found to have Hirschsprung disease, imbalanced hemivertebrae in the 2 lowest thoracic vertebral bodies, and a small right kidney. Brain MRI at age 3 showed decreased volumes of the frontal and parietal lobes, thinning of the corpus callosum, and ventricular dilatation. Other features included malformed large ears, an inferiorly curved penis, bifid scrotum, cryptorchidism, and other thoracic malformations. Skin biopsy showed reduced number of hypoplastic hair follicles. At 4 years of age, he became bedridden and showed almost no response to people. The skin was highly desquamated, similar to that seen in ichthyosis, the nails were thick and deformed, and he had persistent corneal erosions and opacification. There was no family history of the disorder.
Wang et al. (2014) reported a 22-year-old Han Chinese man who was born with nonscarring total alopecia and developed lamellar desquamation on his limbs at 3 years of age, particularly the pretibial area, which later progressed to the entire body. He had photophobia due to corneal scarring and neovascularization. There was prominent pachyonychia as well as palmoplantar keratoderma extending to the dorsa of the palms and soles, resulting in flexion contracture of the left third finger by the age of 14 years. He had mild hyperkeratosis at the angles of the lips and in the perianal area. In addition, he had bilateral inguinal hernias. At 22 years of age, he had short stature and was underweight, but psychomotor development was normal. Histopathologic examination of the ichthyosiform lesions revealed nonspecific features, including orthohyperkeratosis and acanthosis, with an inflammatory infiltrate in the upper dermis. The patient's mother exhibited milder hyperkeratosis involving her right lower leg in a linear mosaic pattern, whereas his father and sister were unaffected.
Megarbane and Megarbane (2011) reviewed X-linked IFAP syndrome. Congenital alopecia, ichthyosis, and photophobia were present in 100% of reported male patients, whereas the various associated features were present in 8 to 46% of patients. The authors stated that management largely consisted of topical keratolytics, urea preparations, and emollients, although some improvement in skin lesions and corneal erosions might be seen with oral retinoid therapy. Because corneal vascularization was relentless in affected boys and unresponsive to topical corticosteroids, intensive lubrication of the ocular surface was the mainstay of therapy.
Corujeira et al. (2013) reported a 5-month-old boy with severe findings of IFAP/BRESHECK syndrome. The patient had follicular ichthyosis, atrichia, photophobia, brain anomalies, global developmental delay, hypotonia, Hirschsprung disease, and kidney hypoplasia. He also had weight, height, and head circumference all below the 5th percentile. He presented with recurrent cutaneous infections by methicillin-resistant Staphylococcus aureus and recurrent urinary tract infections. Two additional features, congenital rectourethral fistula and severe hypogammaglobulinemia with a low B-lymphocyte count, had not previously been seen in this disorder. The patient was treated for the latter condition with intravenous immunoglobulin with good clinical response.
Female Carriers
The diagnosis of IFAP syndrome was established by Konig and Happle (1999) in a 1-year-old boy with congenital hairlessness, generalized ichthyotic skin changes with follicular hyperkeratoses, and photophobia. They had an opportunity to delineate the phenotype in female carriers. A 2-year-old sister had atrophoderma and ichthyotic skin lesions arranged in a linear pattern and a large noncicatricial bald spot on her scalp. Similarly, the mother had linear lesions of scaling and atrophy as well as circumscribed hairless areas involving the scalp, axillary region, and lower legs. Striking asymmetric distribution of axillary hair in the mother was pictured, this being part of patchy hypotrichosis involving predominantly the left side of her body. Sweat testing by means of iodine starch-reaction visualized hypohidrotic linear lesions corresponding to the areas of hyperkeratosis and atrophy. In both the mother and the daughter the lesions followed the lines of Blaschko, whereas the boy was diffusely affected. Family history showed that the boy's maternal uncle, who had died at age 1 year, was affected with the same disorder. Moreover, the maternal grandmother reportedly had bald patches on her scalp and very dry skin. Thus, the X-linked recessive inheritance appears to be established by the finding of signs of lyonization in heterozygous women.
Hamm et al. (1991) described the disorder in an 18-month-old male infant. They suggested that the disorder may be X-linked recessive because all 8 cases from 5 families had been male.
Keyvani et al. (1998) concluded that since all patients with IFAP had been male, and because in 1 family 2 brothers sharing the same mother were probably affected (Martino et al., 1992), X-linked inheritance was most likely.
Cambiaghi et al. (2002) reported 2 unrelated female patients with complete IFAP syndrome. Both patients exhibited diffuse distribution of skin lesions without linear arrangement along the lines of Blaschko, suggesting that the clinical findings were not due to patterns of X inactivation. Cambiaghi et al. (2002) asserted that an X-linked recessive pattern of inheritance is unlikely in these patients, and that a different mode of transmission or genetic heterogeneity should be considered for IFAP.
Keyvani et al. (1998) concluded that when stringent diagnostic criteria were applied, only 10 patients from 8 families with the IFAP syndrome had been reported.
Happle (2004) suggested that there may be as many as 3 distinct forms of IFAP: the classic form in which only boys show the full-blown syndrome and female carriers have a linear pattern of involvement reflecting functional X-chromosome mosaicism; a 'psoriasiform' type represented by the patients reported by Megarbane et al. (2004); and a form in which females display the complete IFAP syndrome as in the patients reported by Cambiaghi et al. (2002).
By linkage analysis in 2 families segregating IFAP, Oeffner et al. (2009) mapped the disease locus to a 5.4-Mb region between DXS989 and DXS8019 on chromosome Xp22.13-p22.11.
In affected members of 3 multigeneration pedigrees segregating IFAP syndrome as well as in 2 unrelated affected patients, all of European descent, Oeffner et al. (2009) identified missense mutations in the MBTPS2 gene. One of the unrelated patients was a member of an affected family described by Boente et al. (2000), and the other had an affected brother. In 3 of the families, affected males mainly displayed the IFAP triad of symptoms comprising total alopecia, ichthyotic scaling (sometimes with psoriasiform plaques), and mild or severe photophobia (see 300294.0001, 300294.0002, 300294.0005). In the other 2 families, males had a more severe phenotype. In 1 of these families, with an R429H mutation (300294.0003), additional features included cleft palate, cleft hands, butterfly vertebrae, absence of a kidney, bilateral inguinal hernia, omphalocele, stenosis of small intestine, Hirschsprung disease, microcephaly, arachnoid cyst, Arnold-Chiari malformation type I, thoracolumbar hydromyelia, seizures, psychomotor retardation, retrognathia, deficient growth, atrial septal defect, arterial hypertension, recurrent infections of upper airways, hypospadias, choanal stenosis, and death by age 2 years. In the other family, with an F475S mutation (300294.0004), males had the additional features of seizures, mental retardation, and inguinal hernia. Female carriers in all families were either phenotypically normal or showed rather mild symptoms such as asymmetric distribution of body hair, patchy alopecia, or linear lesions of follicular ichthyosis after the lines of Blaschko. Oeffner et al. (2009) showed that deficiency of MBTPS2 (300294) due to mutations in the MBTPS2 gene impairs the cholesterol homeostasis and ability to cope with endoplasmic reticulum (ER) stress. Functional studies with the mutations showed that those resulting in the lowest residual MBTPS2 activity corresponded with the most severe phenotypes.
In a 26-year-old Ashkenazi Jewish man and a 28-year-old Caucasian man with the typical IFAP triad, Oeffner et al. (2011) identified an intronic mutation in the MBTPS2 gene (300294.0007). Additional features in both patients included short stature, inguinal hernia, and thickened dystrophic nails.
In a Japanese boy with a clinical diagnosis of BRESHECK syndrome, Naiki et al. (2012) identified an R429H mutation in the MBTPS2 gene (300294.0003). His unaffected mother was heterozygous for the mutation. The same mutation had previously been reported in a patient with severe IFAP (Oeffner et al., 2009), indicating that the 2 disorders are allelic and represent a phenotypic spectrum.
In a 22-year-old Han Chinese man with ichthyosis, total alopecia, photophobia, short stature, inguinal hernia, and pachyonychia, who also exhibited the Olmsted syndrome (see 300918)-like features of palmoplantar and periorificial keratoderma, Wang et al. (2014) performed whole-exome sequencing and identified the same intronic mutation in the MBTPS2 gene (300294.0007) that had previously been identified in 2 IFAP patients by Oeffner et al. (2011). The mutation was confirmed by Sanger sequencing to be heterozygous in the patient's more mildly affected mother, and was not found in his unaffected father or sister or in 200 unrelated ethnically matched controls. Wang et al. (2014) designated the phenotype in their patient as 'IFAP with Olmsted syndrome-like features' and questioned whether X-linked Olmsted syndrome represented an independent condition or a severe form of IFAP.
In a 5-month-old Portuguese boy with severe findings of IFAP/BRESHECK syndrome, Corujeira et al. (2013) identified a recurrent missense mutation in the MTBTPS2 gene (R429H; 300294.0003). In addition to typical features of the disorder, including follicular ichthyosis, atrichia, photophobia, brain anomalies, global developmental delay, Hirschsprung disease, and kidney hypoplasia, the patient had severe hypogammaglobulinemia and congenital rectourethral fistula. The authors noted that among the 6 reported patients (including theirs) with the R429H mutation, 4 had Hirschsprung disease; they proposed that this defect might be a phenotypic marker for this variant because other patients with IFAP/BRESHECK syndrome have not been reported with Hirschsprung disease.
Boente, M. C., Bibas-Bonet, H., Coronel, A. M., Asial, R. A. Atrichia, ichthyosis, follicular hyperkeratosis, chronic candidiasis, keratitis, seizures, mental retardation and inguinal hernia: a severe manifestation of IFAP syndrome? Europ. J. Derm. 10: 98-102, 2000. [PubMed: 10694306]
Cambiaghi, S., Barbareschi, M., Tadini, G. Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome in two unrelated female patients. J. Am. Acad. Derm. 46: S156-S158, 2002. [PubMed: 12004300] [Full Text: https://doi.org/10.1067/mjd.2002.112930]
Corujeira, S., Agueda, S., Monteiro, G., Canelhas, A., Sampaio, M., Rocha, R., Leao, M. Expanding the phenotype of IFAP/BRESECK syndrome: a new case with severe hypogammaglobulinemia. Europ. J. Med. Genet. 56: 603-605, 2013. [PubMed: 24090718] [Full Text: https://doi.org/10.1016/j.ejmg.2013.09.005]
Eramo, L. R., Esterly, N. B., Zieserl, E. J., Stock, E. L., Herrmann, J. Ichthyosis follicularis with alopecia and photophobia. Arch. Derm. 121: 1167-1174, 1985. [PubMed: 4037843]
Freire-Maia, N., Pinheiro, M. Ectodermal Dysplasias: A Clinical and Genetic Study. New York: Alan R. Liss (pub.) 1984. Pp. 126-127.
Hamm, H., Meinecke, P., Traupe, H. Further delineation of the ichthyosis follicularis, atrichia, and photophobia syndrome. Europ. J. Pediat. 150: 627-629, 1991. [PubMed: 1915513] [Full Text: https://doi.org/10.1007/BF02072621]
Happle, R. What is IFAP syndrome? Am. J. Med. Genet. 124A: 328 only, 2004. [PubMed: 14708110] [Full Text: https://doi.org/10.1002/ajmg.a.20353]
Keyvani, K., Paulus, W., Traupe, H., Kiesewetter, F., Cursiefen, C., Huk, W., Raab, K., Orth, U., Rauch, A., Pfeiffer, R. A. Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome: clinical and neuropathological observations in a 33-year-old man. Am. J. Med. Genet. 78: 371-377, 1998. [PubMed: 9714442] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980724)78:4<371::aid-ajmg13>3.0.co;2-f]
Konig, A., Happle, R. Linear lesions reflecting lyonization in women heterozygous for IFAP syndrome (ichthyosis follicularis with atrichia and photophobia). Am. J. Med. Genet. 85: 365-368, 1999. [PubMed: 10398262] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990806)85:4<365::aid-ajmg12>3.0.co;2-#]
MacLeod, J. M. H. Three cases of 'ichthyosis follicularis' associated with baldness. Brit. J. Derm. 21: 165-189, 1909.
Martino, F., D'Eufemia, P., Pergola, M. S., Finocchiaro, R., Celli, M., Giampa, G., Frontali, M., Giardini, O. Child with manifestations of dermotrichic syndrome and ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome. Am. J. Med. Genet. 44: 233-236, 1992. [PubMed: 1456297] [Full Text: https://doi.org/10.1002/ajmg.1320440222]
Megarbane, H., Megarbane, A. Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome. Orphanet J. Rare Dis. 6: 29, 2011. Note: Electronic Article. [PubMed: 21600032] [Full Text: https://doi.org/10.1186/1750-1172-6-29]
Megarbane, H., Zablit, C., Waked, N., Lefranc, G., Tomb, R., Megarbane, A. Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome: report of a new family with additional features and review. Am. J. Med. Genet. 124A: 323-327, 2004. [PubMed: 14708109] [Full Text: https://doi.org/10.1002/ajmg.a.20352]
Naiki, M., Mizuno, S., Yamada, K., Yamada, Y., Kimura, R., Oshiro, M., Okamoto, N., Makita, Y., Seishima, M., Wakamatsu, N. MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Am. J. Med. Genet. 158A: 97-102, 2012. [PubMed: 22105905] [Full Text: https://doi.org/10.1002/ajmg.a.34373]
Oeffner, F., Fischer, G., Happle, R., Konig, A., Betz, R. C., Bornholdt, D., Neidel, U., Boente, M. del C., Redler, S., Romero-Gomez, J., Salhi, A., Vera-Casano, A., Weirich, C., Grzeschik, K.-H. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am. J. Hum. Genet. 84: 459-467, 2009. [PubMed: 19361614] [Full Text: https://doi.org/10.1016/j.ajhg.2009.03.014]
Oeffner, F., Martinez, F., Schaffer, J., Salhi, A., Monfort, S., Oltra, S., Neidel, U., Bornholdt, D., van Bon, B., Konig, A., Happle, R., Grzeschik, K.-H. Intronic mutations affecting splicing of MBTPS2 cause ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome. (Letter) Exp. Derm. 20: 447-456, 2011. [PubMed: 21426410] [Full Text: https://doi.org/10.1111/j.1600-0625.2010.01238.x]
Reish, O., Gorlin, R. J., Hordinsky, M., Rest, E. B., Burke, B., Berry, S. A. Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/BRESHECK): new X-linked syndrome? Am. J. Med. Genet. 68: 386-390, 1997. [PubMed: 9021007] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970211)68:4<386::aid-ajmg2>3.0.co;2-k]
Wang, H. J., Tang, Z. L., Lin, Z. M., Dai, L. L., Chen, Q., Yang, Y. Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient. Clin. Exp. Derm. 39: 158-161, 2014. [PubMed: 24313295] [Full Text: https://doi.org/10.1111/ced.12248]
Zeligman, I., Fleisher, T. L. Ichthyosis follicularis. Arch. Derm. 80: 413-420, 1959. [PubMed: 13847228] [Full Text: https://doi.org/10.1001/archderm.1959.01560220023005]