NORD gratefully acknowledges John M. Graham, JR., M.D., Sc.D., Pediatric Consultant in Clinical Genetics and Dysmorphology, Department of Pediatrics, Cedars-Sinai Medical Center, for assistance in the preparation of this report.
Hallermann-Streiff syndrome (HSS) is a rare genetic disorder that is primarily characterized by distinctive malformations of the skull and facial (craniofacial) region; sparse hair (hypotrichosis); eye abnormalities; dental defects; degenerative skin changes (atrophy), particularly in the scalp and nasal regions; and proportionate short stature. Characteristic craniofacial features include a short, broad head (brachycephaly) with an unusually prominent forehead and/or sides of the skull (dyscephaly); a small, underdeveloped lower jaw (hypoplastic mandible); a narrow, highly arched roof of the mouth (palate); and a thin, pinched, tapering nose. Many affected individuals also have clouding of the lenses of the eyes at birth (congenital cataracts or corneal stromal opacities); unusually small eyes (microphthalmia); and/or other ocular abnormalities (glaucoma, retinal detachments). Dental defects may include natal or neonatal teeth, delayed tooth eruption, enamel hypoplasia, absent permanent teeth (hypodontia or partial adontia), abnormal tooth development resulting in short roots and early loss of teeth, and/or improper alignment of teeth. In almost all cases, HSS has appeared to occur randomly for unknown reasons (sporadically), and this syndrome is thought to be the result of a new change to genetic material (mutation).Introduction
Hallermann-Streiff syndrome was first described in the medical literature in 1893. The disorder was named for two investigators who later independently reported cases of the syndrome, recognizing it as a distinct disease entity.
Associated symptoms and signs vary greatly in range and severity from case to case. The principal features of Hallermann-Streiff syndrome include abnormalities of the skull (cranium) and certain bones of the face (known as dyscephaly); distinctive facial features; ocular defects; dental anomalies; and/or proportionate short stature. In many cases, additional abnormalities are also present.
Many affected infants have an unusually shaped skull, with abnormal shortness of the head (brachycephaly) and prominence of the forehead and/or sides of the skull (frontal and/or parietal bossing). In some cases, the head may also be relatively small (microcephaly) and the cheekbones may be underdeveloped (malar hypoplasia). In addition, there is typically abnormal widening of the fibrous joints (sutures) between certain bones of the skull and delayed closure of the two “soft spots” (fontanelles) at the front and back of the cranium.
Affected individuals also often have a disproportionately small face; a high, narrow roof of the mouth (palate); and/or a small lower jaw (micrognathia) with receding chin (retrognathia). The nose is typically quite narrow and pointed; with a narrow nasal bridge, small nostrils and underdeveloped nasal cartilage that tends to become more convex (beaked) with age. The underdevelopment of the jaw and nose may result in upper airway obstruction and breathing difficulties in young children. In addition, many people with this syndrome have very sparse hair (hypotrichosis), particularly of the scalp, eyelashes, eyebrows, beard, pubic hair, and hair under the arms. Degenerative skin changes (atrophy) are also often present and largely limited to the scalp and nose. Due to such changes, the skin in these regions may appear unusually taut and thin, and regional blood vessels may seem unusually pronounced. Nasal lipofilling has been used to treat the atrophy of the nasal skin, resulting in improvement in nasal skin color and texture.
The craniofacial abnormalities associated with the disorder, such as small nostrils and glossoptosis, can cause obstruction of the upper airway, particularly during the newborn period and infancy. Glossoptosis refers to downward displacement or retraction of the tongue that may occur secondary to abnormal smallness of the lower jaw (micrognathia). A narrow upper airway may lead to feeding, swallowing, and/or breathing difficulties; severe early respiratory infections; episodes in which there is absence of spontaneous breathing (apnea); anesthetic complications; and potentially life-threatening complications in severe cases. Abnormal softening of cartilage of the windpipe (tracheomalacia) has also been reported in some cases, which may further complicate swallowing and breathing difficulties. In addition, there have also been reports in which respiratory insufficiency (e.g., due to a narrow upper airway and/or tracheomalacia) has resulted in enlargement and strain of the lower right chamber (ventricle) of the heart (cor pulmonale) and possibly the left ventricle as well, leading to heart failure. Heart failure is an inability of the heart to pump enough blood to meet the body’s requirements for oxygen and other nutrients.
Most individuals with HSS have ocular abnormalities. The most common ocular finding is clouding (opacity) of the lenses of both eyes at birth (congenital bilateral cataracts). According to reports in the medical literature, the cataracts, which consist of whitish, milky lens masses, may gradually spontaneously resolve (spontaneous cataract absorption) in some cases. Many individuals with this disorder also have abnormal smallness of both eyes (bilateral microphthalmia) of varying severity and/or unusually deep-set eyes (enophthalmos). As a result of these small deeply-seated eyes, patients may appear to have small, droopy eyelids (blepharoptosis). The edges of the eyelids may appear to turn inwards, particularly on the lower side (lower lid entropion) so that the eyelashes rub against the eye surface (cornea) leading to irritation, erosions and corneal opacities. Some eye experts suggest corneal stromal opacities, which are ill defined and bilateral with clear stroma between the opacities might be a hallmark feature of this condition. In some cases, additional ocular defects may also be present, such as abnormal deviation of one eye in relation to the other (strabismus); involuntary, rapid, rhythmic eye movements (nystagmus); unusual blueness of the “whites” of the eyes (blue sclera); abnormally elevated pressure of the fluid of the eyes (glaucoma); retinal detachments; down-slanting eyelids (palpebral fissures); or malformed orbital bones and/or other findings. Such ocular defects may result in varying degrees of visual impairment or, in some cases, blindness.
Hallermann-Streiff syndrome is frequently characterized by dental abnormalities. These may include the eruption of teeth before or shortly after birth (natal or neonatal teeth), which may be misdiagnosed as supernumerary teeth. There is also delayed eruption of permanent teeth, abnormal tooth development, with severely undeveloped roots leading to early loss of permanent teeth and partially developed crowns, improper contact between the teeth of the upper jaw and those of the lower jaw (malocclusion), and/or persistence of the primary (deciduous) teeth. Additional dental defects may include absence of permanent teeth (hypodontia or anodontia), and/or severe, early tooth decay with enamel hypoplasia.
In approximately one third of reported cases, infants with HSS are born prematurely and/or have a low birth weight. About two thirds of affected individuals have growth deficiency after birth and associated proportionate short stature.
In some cases, additional physical abnormalities have also been reported in association with the disorder. Some affected males may have decreased testicular function (hypogonadism), undescended testes (cryptorchidism), and/or abnormal placement of the urinary opening of the penis (hypospadias). Skeletal abnormalities have also been reported in some cases, such as widely flared shoulder blades (winged scapula), abnormal curvature of the spine (lordosis or scoliosis), abnormal depression of the breastbone (pectus excavatum), and/or webbing of fingers and/or toes (syndactyly). Radiological findings in infants can include a large, poorly ossified skull with decreased ossification in the sutural areas, multiple Wormian bones within sutures, and severe mid-facial hypoplasia with a prominent nasal bone, small teeth, thin and gracile long bones with poor demarcation of the cortex from the medullary portion, neonatal bowing of the radius and ulna and widening at the metaphyseal ends of the long bones. Some affected infants may also have vitiligo, a condition characterized by irregular patches of skin that lack pigmentation. In addition, in rare cases, various structural heart malformations (congenital heart defects) have been reported. Such congenital heart defects have included an abnormal opening in the partition (septum) that separates the lower or upper chambers of the heart (ventricular or atrial septal defects) or abnormal narrowing of the opening between the pulmonary artery and the right ventricle of the heart (pulmonary stenosis).
In most cases, children with this disorder have normal intelligence; however, intellectual disability has been reported in approximately 15 percent of cases. In rare instances, neurologic abnormalities have been noted, including hyperactivity; seizures, and/or choreoathetosis, a condition characterized by abnormal, involuntary, irregular jerky motions and slow, writhing movements. With more patients undergoing MRI studies, various structural abnormalities of the brain have been reported. One as such case showed the absence of the corpus callosum (the thick band of nerve fibers that connects the right and left halves of the brain).
In almost all reported cases, Hallermann-Streiff syndrome has occurred randomly for unknown reasons (sporadically), most likely due to a new spontaneous dominant genetic change (mutation). There have been reports of patients with this disorder reproducing successfully and bearing multiple normal children. From families with an affected child, there is little evidence for this being a recessively inherited disorder in which both parents are carriers (normal looking but carry the mutation). Therefore, the mode of inheritance of this disorder remains elusive making it difficult to determine the exact recurrent risk.
Hallermann-Streiff syndrome bears some similarity to some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (caused by de novo point mutations in the LMNA gene) and mandibuloacral dysplasia (recessive disorders resulting from mutations in LMNA and ZMPSTE24). ZMPSTE24 and ICMT encode proteins involved in posttranslational processing of lamin A. Sequencing of the genes LMNA, ZMPSTE24 and ICMT in 8 patients with Hallermann-Streiff syndrome revealed no evidence that this disorder is a type of laminopathy, but these conditions remain part of the differential diagnosis, particularly when autosomal recessive inheritance is suspected.
Hallermann-Streiff syndrome appears to affect males and females in relatively equal numbers. More than 150 cases have been reported in the medical literature.
Hallermann-Streiff syndrome may be suspected shortly after birth or during the first year of life by the identification of characteristic physical findings and symptoms. The diagnosis may be confirmed by thorough clinical evaluation; a detailed patient history; and specialized tests (e.g., radiographic, ophthalmologic, and dental studies) that may help to detect and characterize the abnormalities associated with this disorder. Congenital cataracts with unusually small eyes (microphthalmia) are important findings for the initial diagnosis of Hallermann-Streiff syndrome, but other disorders must be considered as part of the differential diagnosis.
The treatment of Hallermann-Streiff syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians, craniofacial surgeons, eye specialists (ophthalmologists), dental specialists, and/or other health care professionals.
For infants with feeding and respiratory difficulties, early disease management should include monitoring of breathing, consideration of tracheostomy (creation of an opening through the neck into the windpipe into which a tube is inserted, to help maintain an effective airway), and various supportive measures to improve feeding and ensure sufficient intake of nutrients. In addition, early surgical removal of cataracts may be recommended to help preserve vision; however, some investigators indicate that the frequency of spontaneous cataract absorption (see “Symptoms”) may be underestimated in those with Hallermann-Streiff syndrome, suggesting that it may occur in up to 50 percent of untreated patients followed up through age 5 years. These physicians may advise waiting for possible spontaneous cataract absorption in selected cases, particularly for patients with significant microphthalmia. Regular close ophthalmology follow-up is strongly recommended to identify and treat other eye abnormalities like nystagmus, ptosis and entropion, which may require surgical intervention to avoid developing a lazy eye (amblyopia) and allow appropriate development of vision. Further investigation is needed regarding the frequency of spontaneous cataract absorption and optimal treatment approaches.
With respect to dental anomalies, it is important to note that the natal/neonatal teeth (teeth present at birth) may be incorrectly diagnosed as supernumerary (extra) teeth and there may be a tendency to extract them. However, apart from their role in mastication (chewing), teeth are also important for maintaining the vertical dimensions of the oral cavity, and the loss of teeth may worsen the glossoptosis (posterior location of the tongue) by over closure of the already small lower jaw (micrognathia). Whenever possible every effort should be made to preserve these prematurely erupted deciduous (baby) teeth to facilitate future nutritional intake and prevent unfavorable sequelae, until the existence of successional permanent teeth can be confirmed. Also, because individuals with Hallermann-Streiff syndrome have malformed teeth with abnormal roots and enamel hypoplasia, they are predisposed to developing severe dental caries making it imperative to ensure good dental hygiene. It may be difficult to perform root canal treatment and other therapies to preserve a tooth with underdeveloped roots, and therefore these patients need appropriate, frequent pediatric dental evaluations.
Recommended disease management may also include surgical reconstruction of certain craniofacial malformations (particularly the mandibular and nasal region) at the appropriate age. Some affected individuals may have a risk of anesthetic complications, since endotracheal intubation and laryngoscopy may be difficult due to upper airway obstruction. Intubation may be required for the delivery of oxygen or anesthetic gases during surgery. A viewing tube (laryngoscope) is used before intubation to help identify the vocal cords. A breathing (endotracheal) tube is then passed through the mouth down the throat and into the windpipe. This potential anesthetic risk must be taken into consideration by surgeons, pediatric anesthesiologists, and other health care providers when making decisions concerning surgery.
For some affected infants and children with heart defects, medical treatment, surgical intervention, and/or other surgical measures may also be recommended. The specific surgical procedures performed will depend upon the size, nature, severity, and/or combination of the anatomical abnormalities, their associated symptoms, and other factors.
Early intervention is important to ensure that children with Hallermann-Streiff syndrome reach their potential. Special services that may be beneficial include special remedial education, special social support, physical therapy, and other medical, social, and/or vocational services.
Genetic counseling may also be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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