Fontaine Progeroid Syndrome

A number sign (#) is used with this entry because of evidence that Fontaine progeroid syndrome (FPS) is caused by heterozygous mutation in the SLC25A24 gene (608744) on chromosome 1p36.

Description

Fontaine progeroid syndrome is characterized by prenatal and postnatal growth retardation, decreased subcutaneous fat tissue, sparse hair, triangular face, widely open anterior fontanel, convex and broad nasal ridge, micrognathia, craniosynostosis in some patients, and early death in many (summary by Writzl et al., 2017).

Nomenclature

Fontaine progeroid syndrome and Gorlin-Chaudhry-Moss syndrome (GCMS) were originally thought to be separate disorders. Ehmke et al. (2017) reported mutations in SLC25A24 in patients clinically diagnosed with GCMS. Because the patients originally reported by Gorlin et al. (1960) and Ippel et al. (1992) are deceased and not available for sequence analysis, GCMS is now considered a milder form of FPS (Hennekam, 2018). See HISTORY.

Clinical Features

Petty et al. (1990) described what they considered to be a newly recognized form of congenital progeroid syndrome in a 5-year-old girl. They suggested that the 46-year-old woman reported by Wiedemann (1979) had the same syndrome. Common manifestations included pre- and postnatal growth retardation, markedly diminished subcutaneous fat, wrinkled skin, abnormally scant hair growth, hypoplastic distal phalanges with hypoplastic nails, umbilical hernia, large open anterior fontanel, and normal cognitive and motor development. Both patients had a prematurely aged appearance since birth. Petty et al. (1990) noted that patients with Wiedemann-Rautenstrauch syndrome (WRS; 264090) show similarities to their patient, but differ by the presence of natal teeth, large hands and feet with long, tapering digits, developmental delay, and neurologic impairment.

Rodriguez et al. (1999) reported a severe prenatal form of progeria. Marked intrauterine growth retardation (IUGR) and oligohydramnios had been detected at 32 weeks' gestation by ultrasonography, and the patient was born by cesarean section at 35 weeks. She died 7 hours after birth with features including premature aging, absence of subcutaneous fat, brachydactyly, absent nipples, hypoplastic external genitalia, and abnormal ear lobes. The authors designated this case as a prenatal form of Hutchinson-Gilford progeria syndrome (HGPS; 176670). However, Faivre et al. (1999) reported a similarly affected female neonate and stated that HGPS was an 'inappropriate' diagnosis for both their own patient and the patient reported by Rodriguez et al. (1999). Despite some overlap in clinical manifestations, Faivre et al. (1999) also thought it unlikely that their infant had WRS, also known as neonatal progeroid syndrome. Rodriguez and Perez-Alonso (1999) defended the 'diagnosis of progeria syndrome [as] the only one possible.'

Castori et al. (2009) described a male infant born with marked IUGR and oligohydramnios, for which he was delivered by cesarean section at 32 weeks' gestation. At birth he was cyanotic and hypotonic, with severe respiratory distress, and he died at 20 hours after birth from cardiopulmonary failure. Postmortem examination showed brachycephaly, wide anterior fontanel, hypertelorism, midface hypoplasia with depressed periorbital area, short nose with broad base and anteverted nares, and low-set ears with flattened helix. There was a generalized deficiency of subcutaneous fat, and his scalp hair showed an unusual distribution, being sparse in the parietal area bilaterally. The digits of all 4 limbs were shortened and markedly tapered with nail hypoplasia/aplasia. Abdominal muscles were severely hypoplastic and the overlying skin was mildly redundant. In addition, he had micropenis, hypoplasia of the scrotum, and bilateral cryptorchidism. X-ray showed synostotic brachycephaly due to premature fusion of the coronal sutures, universal platyspondyly with superior and inferior notching of multiple vertebral bodies, and hypoplasia/aplasia of the distal phalanx of all digits. Dissection revealed pachygyria and cerebellar hypoplasia, as well as intestinal malrotation and multiple volvuli. Noting the triad of craniosynostosis, anonychia, and extensive abdominal muscle hypoplasia in this patient, the authors concluded that the disorder was consistent with what they designated 'Fontaine-Farriaux syndrome.'

Adolphs et al. (2011) reported a 7-year-old Hungarian girl with GCMS who underwent frontofacial advancement by internal distraction for functional and psychosocial amelioration of her complex craniofacial malformation. In addition to brachycephaly with severe midface hypoplasia and retrusion, she had short eyebrows and palpebral fissures, hypertrichosis of the scalp and trunk with low frontal hairline, hyperopia, dental anomalies, and hypoplasia of the labia majora, and she was given a diagnosis of Gorlin-Chaudhry-Moss syndrome. Her postoperative course was complicated by a necrotizing soft tissue infection of the scalp.

Ehmke et al. (2017) studied 5 unrelated girls, including the Hungarian girl previously reported by Adolphs et al. (2011) (patient 2), who all exhibited brachycephaly, broad forehead, depressed supraorbital ridge, midface hypoplasia, prognathia or tongue protrusion, low anterior and posterior hairlines, hypertrichosis, and wrinkled skin. Other features included large anterior fontanel, coarse scalp hair, short downslanting palpebral fissures, and low-set dysplastic ears. All had failure to thrive, and 4 of the 5 showed IUGR and postnatal short stature, with reduced subcutaneous fat tissue and dermal translucency. In addition, 4 exhibited coronal craniosynostosis, oligodontia and/or microdontia, and small nails; short distal phalanges and syndactyly were also present in 3, and 3 had conductive hearing impairment. Four had umbilical hernia, and 2 also had hypoplasia of the abdominal wall muscles. Four of the 5 patients were alive at ages 5, 5.5, 7, and 14 years, but a Turkish girl (patient 4) died at 20 months after a urinary tract infection. Two of the girls had initially been diagnosed with neonatal progeroid syndrome (WRS), but the authors stated that the 5 girls showed the typical hallmarks of GCMS.

Writzl et al. (2017) studied 2 boys and 2 girls with a progeroid appearance. The 2 girls were previously reported by Rodriguez et al. (1999) (patient 3) and Faivre et al. (1999) (patient 2), and 1 of the boys was reported by Castori et al. (2009) (patient 4). All presented with pre- and postnatal growth retardation as well as an aged appearance characterized by decreased subcutaneous fat, wrinkled skin, and prominent veins. Other features included wide fontanels, abnormal scalp hair pattern, triangular face, midface hypoplasia, convex nasal ridge, micrognathia, low-set dysplastic ears, small distal phalanges, and small nails. Umbilical hernia was present in 2 patients, and another had abdominal muscle hypoplasia. Cryptorchidism was present in both boys, and 1 also had micropenis and hypoplastic scrotum. Two patients had craniosynostosis, with premature fusion of coronal sutures in both and parietotemporal synostosis in 1. All 4 patients died within the first year of life: patients 3 and 4 from respiratory distress, at 7 hours and 20 hours after birth, respectively; patient 1 from pulmonary hypertension at age 6 months; and patient 2 from sepsis at age 7 months. For historic reasons, the authors designated the congenital progeroid disorder in these patients as Fontaine syndrome, noting that a similarly affected patient was first described by Fontaine et al. (1977); Writzl et al. (2017) also stated that the phenotype was likely to represent the same entity as that described by Petty et al. (1990).

Molecular Genetics

By whole-exome or whole-genome sequencing in 4 unrelated girls with a progeroid appearance, including the Hungarian girl with GCMS reported by Adolphs et al. (2011), Ehmke et al. (2017) identified heterozygosity for 2 different de novo missense mutations in the SLC25A24 gene, both occurring at the same codon: R217H (608744.0001) in 3 patients, and R217C (608744.0002) in 1 patient. Sanger sequencing in a similarly affected fifth girl revealed heterozygosity for the R217H variant, which had also occurred de novo. Neither mutation was found in the ExAC, gnomAD, or 1000 Genomes Project databases. Noting that the patients studied by Writzl et al. (2017) showed overlapping clinical features and carried the same mutations in the SLC25A24 gene, but exhibited early demise in contrast to their patients, 4 of whom were alive and over 5 years of age, Ehmke et al. (2017) suggested that variation in the function of other genes involved in mitochondrial function, as well as other genetic, epigenetic, or environmental influences might explain the variability of the phenotype.

In 2 patients with Fontaine syndrome, including a Slovenian boy (patient 1) and a French girl (patient 2) who was originally reported by Faivre et al. (1999), and their parents, Writzl et al. (2017) performed whole-exome sequencing and identified heterozygosity for the same de novo R217H mutation in the SLC25A24 gene in both patients. Whole-genome sequencing in a similarly affected Spanish girl (patient 3), originally reported by Rodriguez et al. (1999), revealed heterozygosity for a de novo R217C mutation in the SLC25A24 gene. Screening SLC25A24 by Sanger sequencing in an Italian boy with Fontaine syndrome (patient 4), previously described by Castori et al. (2009), revealed the same de novo variant as in the first 2 patients, R217H. Noting that the patients studied by Ehmke et al. (2017) carried the same SLC25A24 mutations and also resembled their patients except for some facial characteristics and early demise, Writzl et al. (2017) suggested that variations in function of other genes involved in mitochondrial functioning, other genetic and epigenetic influences, and environmental influences might play a role.

History

Gorlin et al. (1960) described 2 sisters with craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, genital hypoplasia, and ocular, dental, and digital anomalies. The parents were not known to be related. The same sisters were reported by Feinberg (1960) as instances of the Weill-Marchesani syndrome (277600), which was clearly an incorrect diagnosis. Ippel et al. (1992) provided follow-up of the 2 sisters reported by Gorlin et al. (1960), G.G. and N.G., then aged 36 and 34, respectively. Although there had been slight coarsening of the facial features with time, the overall clinical picture had not changed. Ippel et al. (1992) reported 2 additional patients, both female, aged 4 and 33 years. All 4 patients had conductive hearing loss, hypertrichosis, coarse hair, and low frontal hairline. The 2 new patients had very short distal phalanges of fingers and toes. As in the original patients, G.G. and N.G. (as reported by Feinberg, 1960), the skeletal abnormalities included shortened metacarpals and distal phalanges. Parental consanguinity had not been established in any of these patients. Hennekam (2018) stated that the patients reported by Gorlin et al. (1960) and Ippel et al. (1992) are deceased and that their DNA is unavailable for study.

Preis et al. (1995) pointed out phenotypic overlap between GCMS and the Saethre-Chotzen syndrome (101400).

Aravena et al. (2011) described 2 Chilean sisters with features overlapping those of GCMS patients, including intrauterine growth retardation, short stature, brachycephaly, midface hypoplasia, small eyes, downslanting palpebral fissures, epicanthal folds, hypertrichosis, coarse hair, low frontal hairline, nail hypoplasia, patent ductus arteriosus, umbilical hernia, and hypoplastic labia majora. However, the Chilean patients did not have upper eyelid coloboma, hearing loss, or stocky body build, and the proband had cutis aplasia and an occipital mass in the same area, which on autopsy appeared to be an encephalocele. In addition, both sisters had hyperthermia, sweating, and persistent respiratory distress; both died of pneumonia, at ages 5 months and 18 months. Aravena et al. (2011) noted that the sisters' features also overlapped with those of Petty progeroid syndrome, but stated that the overall pattern was more consistent with a diagnosis of GCMS.

Rosti et al. (2013) reported what they considered to be the seventh case of GCMS and reviewed the clinical presentations of previously published patients. Their proband was a Turkish girl who was born with coronal craniosynostosis, which was repaired at 18 months of age, as well as with laryngomalacia, which became asymptomatic by age 3 years. Examination at 4.5 years of age revealed stocky body build, brachy/turricephaly, generalized hypertrichosis with low anterior and posterior hairlines, midface hypoplasia, bilateral upper lid colobomas, hyperopia, small posteriorly rotated ears, and hypoplastic labia majora. Dental evaluation showed microdontia, irregularly shaped and widely spaced teeth, oligodontia, and narrow high-arched palate with medial cleft. She also had bilateral mild conductive hearing loss. Although this patient exhibited the cardinal features of GCMS, she displayed other features not previously reported, including bifid nasal tip, absent flexion crease of thumbs and bilateral single transverse palmar crease, and laryngomalacia. Rosti et al. (2013) suggested that the 7 reported GCMS patients could be divided into 2 subsets with differing facial gestalts: group 'A' included their Turkish case, the Chilean sisters described by Aravena et al. (2011), and the 4-year-old girl reported by Ippel et al. (1992), all of whom exhibited synophrys and a laterally widening and extending eyebrow pattern that forms a 'stair case' descending to the lateral orbital rim and canthus, as well as prominent columella and relatively underdeveloped ala nasi, with bifid nasal tip in some. In addition, these patients had small medial clefts of the palate and cutaneous syndactyly. In contrast, group 'B' patients displayed deeply set eyes, with eyebrows that were underdeveloped medially and showed gradual thinning laterally. Rosti et al. (2013) noted that these subsets might represent different phenotypic expressions of the same molecular entity or distinct molecular entities with significant clinical overlap.

The original patients reported by Gorlin et al. (1960) were sibs born to unaffected parents, suggesting autosomal recessive inheritance. However, Rosti et al. (2013) noted that all 7 patients reported with GCMS have been female with no known parental consanguinity, suggesting a de novo X-linked dominant disorder with male lethality. In that case, the mothers of the affected sisters of Gorlin et al. (1960) and Aravena et al. (2011) might have gonadal mosaicism for the causative mutation.