Hallermann-Streiff Syndrome

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Hallermann-Streiff Syndrome


Disease Entity

Hallermann-Streiff syndrome (HSS) is a very rare genetic disorder that has a characteristic facial appearance, dental abnormalities, hypotrichosis, skin atrophy, proportionate short stature, and ophthalmic features such as microphthalmia and congenital bilateral cataracts. The disease was first discussed by Aubry in the late 1800s, but it was documented as a distinct entity by Hallermann in 1948 and Streiff in 1950.[1]

Epidemiology

To date, approximately 200 cases have been reported worldwide[2]. The inheritance pattern of HSS is ill defined and males and females are equally affected. The vast majority of cases are attributed to sporadic mutations, but there have been a few rare familial cases reported as well. Two cases of monozygotic twins have been described, where 1 set had both twins affected while the other had only 1 twin affected[3].

Etiology

The causative gene for HSS is yet to be determined. Previously, mutations in the GJA1 gene were thought to be contributing to the disease due to a similar phenotype in patients with these mutations; however, this phenotype was ultimately recognized to be different from the typical manifestations found in HSS.[2]

Pathophysiology

The disease appears to be related to a defect involving the second branchial arch during the early gestation period[1]. This may be the basis for the craniofacial abnormalities related to HSS.

Diagnosis

Clinical Features

Craniofacial – previously described as “bird-like” facies, but this terminology is no longer in use.

  • Skull abnormalities include brachycephaly, delayed closure of fontanelles, wide sutures, poor ossification, and mild microcephaly
  • Thin, beaked nose with pinched ridge
  • Micrognathia
  • Temporomandibular joint abnormalities with underdevelopment or displacement of the condyles or displacement of the disk
  • High-arched palate


Skin and hair

  • Hypotrichosis, especially of the scalp, eyebrows, and eyelashes
  • Atrophic skin especially of the scalp, forehead, and nose


Ophthalmic -Present in approximately 90% of patients[4]

  • Bilateral congenital cataracts and microphthalmia are most frequently observed
  • Other features include nystagmus, strabismus, conjunctival defects, corneal abnormalities, retinal detachments, chorioretinal atrophy, and peripapillary choroid atrophy[3]


Dental

  • Missing or deformed teeth
  • Premature eruption and persistence of deciduous teeth
  • Open bite
  • Frequent and/or severe dental caries


Skeletal

  • Short stature that is proportionate in relation to head and extremities
  • Abnormal ossicles that develop from extra ossification centers within the cranium (i.e., Wormian bones) present between cranial sutures
  • Thin ribs and long bones


Cardiac

  • Rare but several reported cases of ventricular and atrial septal defects, Tetralogy of Fallot, pulmonic stenosis, and patent ductus arteriosus


Respiratory

  • Narrow upper airway
  • Glossoptosis


Intellectual disability - Majority of patients have normal mental development; however, some may have intellectual disability.[1]

Clinical diagnosis

Diagnostic criteria have been previously published by Francois and are comprised of the 7 essential features seen in patients affected by HSS.[5] Many cases are diagnosed clinically due to the distinctive craniofacial features observed.

  1. Dyscephalia and “bird-like facies” – consisting of scaphocephaly or brachycephaly, mandibular aplasia, pointed nose
  2. Abnormal dentition – missing and/or deformed teeth, improper implantation of teeth, open bite
  3. Proportionate dwarfism
  4. Hypotrichosis – specifically involving the scalp, eyebrows, and eyelashes
  5. Skin atrophy – localized to head, particularly nose
  6. Bilateral microphthalmia
  7. Congenital cataract – most commonly bilateral; can be focal or complete

Differential diagnosis

Hutchinson-Gilford progeria syndrome (HGPS)

  • HGPS is a rare genetic syndrome that is classically associated with progressive premature aging and particular facial features such as a small face, micrognathia, and a thin, pointed nose with hypotrichosis. It is known to be caused by a substitution in the LMNA gene.[2] It differs from HSS in that patients also have premature atherosclerosis, lipodystrophy, nail dystrophy, and an absence of ocular features[2].


Wiedemann-Rautenstrauch syndrome

  • Wiedemann-Rautenstrauch syndrome, is a rare genetic syndrome that causes premature aging. Patients present with growth restriction, lipodystrophy, and a scalp with little hair and prominent veins.[2] Like HSS, these patients can have a characteristic facial appearance and abnormal dentition; however, they do not usually present with ophthalmic features of HSS such as congenital cataracts or microphthalmia.


Mandibulofacial dysostosis

  • Mandibulofacial dysostosis, also known as Treacher Collins syndrome, is an autosomal dominant craniofacial genetic disorder involving the first and second branchial arches that is caused by mutations in the TCOF1 gene. Some features are shared with HSS such as micrognathia and dental abnormalities, but mandibulofacial dysostosis is distinguishable due to the presence of external ear abnormalities and colobomas of the lower eyelid.[2]


Oculodentodigital Dysplasia (ODDD)

  • ODDD is an autosomal dominant genetic disorder caused by mutations in the GJA1 gene[6]. Similar to HSS, ODDD also presents with hypotrichosis, micrognathia, abnormal dentition, and a small nose; however, ODDD also involves the digits with abnormalities such as syndactyly or hypoplastic phalanges.


Seckel syndrome

  • Seckel syndrome is a rare autosomal recessive genetic disorder characterized by intrauterine growth restriction, proportionate dwarfism, and intellectual disability. Craniofacial features of Seckel syndrome can be distinguished from HSS by the presence of ear malformations and severe microcephaly but no congenital cataracts.[2]

Management

Management of HSS is aimed at addressing the most concerning and debilitating features. This includes ophthalmic, dental, cardiovascular, and respiratory involvement associated with the disease.[1] Regular ophthalmologic examination is recommended in all patients to establish baseline and monitor the ocular manifestations of disease. Some cases have described spontaneous resorption of congenital cataracts; however, surgery is recommended early on to prevent development of amblyopia. Patients are often left aphakic due to severe microcornea and microphthalmia that can occur with HSS.[4] Regular dental examinations are also recommended to prevent frequent dental caries that may be associated with HSS and their resulting complications. Additionally, preventative measures such as optimal oral hygiene and fissure sealants are recommended.[7] Congenital cardiovascular abnormalities, if present, usually require prompt surgical treatment[8]. Lastly, the craniofacial abnormalities along with narrow upper airways seen in these patients frequently lead to the development of obstructive sleep apnea (OSA), pulmonary infection, cor pulmonale, and feeding difficulties.[1] Assessment for these respiratory complications is recommended early on[9]. Because of the deleterious effects of OSA, it is recommended that any HSS patient who admits to snoring or daytime fatigue be immediately referred for a sleep study for further evaluation and treatment, if necessary.[9] Additionally, it is important to note that micrognathia and tracheomalacia may make tracheotomy or intubation difficult in these patients, and this should be taken into account during surgical procedures performed on patients with HSS.[1]

Course and Prognosis

Few formal studies have been conducted to investigate life expectancy of patients with HSS. Respiratory compromise and/or pulmonary infection in these patients can be very severe and risk of death from these complications is noteworthy[1]. Likewise, the severity of OSA in these patients with craniofacial abnormalities can range from mild to life-threatening. OSA that is not managed adequately has been associated with failure to thrive, hypertension, cardiopulmonary failure, and neurological damage. Each of these complications can significantly affect individual patient prognosis. Visual outcomes are often disappointing in patients even following cataract surgery[3]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Mirshekari A, Safar F. Hallermann-Streiff syndrome: A case review. Clinical and Experimental Dermatology 2004;29:477-479. 
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Schmidt J, Wollnik B. Hallermann-Streiff syndrome: A missing molecular link for a highly recognizable syndrome. American Journal of Medical Genetics 2018;178C:398-406. 
  3. 3.0 3.1 3.2 Steele RW, Bass JW. Hallermann-Streiff Syndrome: Clinical and Prognostic Considerations. The American Journal of Diseases of Children 1970;120:462-465. 
  4. 4.0 4.1 Pasyanthi B, Mendonca T, Sachdeva V, Kekunnaya R. Ophthalmologic manifestations of Hallermann-Streiff-Francois syndrome: report of four cases. Eye 2016;30:1268-1271. 
  5. Francois J. A New Syndrome: Dyscephalia with bird face and dental anomalies, nanism, hypotrichosis, cutaneous atrophy, microphthalmia, and congenital cataract. AMA Arch Ophthalmol 1958;60:842–62.
  6. Pizzuti A, Flex E, Mingarelli R, Salpietro C, Zelante L, Dallapiccola B. A Homozygous GJA1 Gene Mutation Causes a Hallermann-Streiff/ODDD Spectrum Phenotype. Human Mutation 2004;23(3):286.
  7. Robotta P, Schafer E. Hallermann-Streiff syndrome: Case report and literature review. Quintessence International 2011;42:331-338. 
  8. (2006) Hallermann-Streiff Syndrome. In: Atlas of Genetic Diagnosis and Counseling. Humana Press.
  9. 9.0 9.1 Cohen MM. Hallermann-Streiff Syndrome: A Review. American Journal of Medical Genetics 1991;41:488-499.