Hutchinson-Gilford Progeria Syndrome (Progeria)

Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is a rare, fatal, autosomal dominant segmental premature aging disease. With an estimated incidence of 1 in 4 million live births and prevalence of 1 in 20 million living individuals, there are an estimated total of 400 children living with progeria in 2018 worldwide. There is no gender, ethnic, or regional bias.

Progeria is caused by a single-base mutation in the LMNA gene, which results in the production of a mutant lamin A protein called progerin . Lamin A is an intermediate filament inner nuclear membrane protein found in most differentiated cells of the body. Without progerin-specific treatment, children with progeria develop premature progressive atherosclerosis and die of heart failure, usually between ages 5 and 20 yr. Progerin is found in increased concentration in skin and the vascular wall of normal older individuals compared to younger individuals, suggesting a role in normal aging.

Clinical Manifestations

Children develop the appearance of accelerated aging, but both clinical and biologic overlaps with aging are segmental, or partial. Physical appearance changes dramatically each year that they age ( Fig. 109.1 ). The descriptions discussed next are roughly in order of clinical appearance.

Dermatologic Changes

Skin findings are often apparent as initial signs of progeria. These are variable in severity and include areas of discoloration, stippled pigmentation, tightened areas that can restrict movement, and areas of the trunk or legs where small (1-2 cm), soft, bulging skin is present. Although usually born with normal hair presence, cranial hair is lost within the first few years, leaving soft, downy, sparse immature hair on the scalp, no eyebrows, and scant eyelashes. Nail dystrophy occurs later in life.

Failure to Thrive

Children with progeria experience apparently normal fetal and early postnatal development. Between several months and 1 yr of age, abnormalities in growth and body composition are readily apparent. Severe failure to thrive ensues, heralding generalized lipoatrophy, with apparent wasting of limbs, circumoral cyanosis, and prominent veins around the scalp, neck, and trunk. The mean weight percentile is usually normal at birth, but decreases to below the 3rd percentile despite adequate caloric intake for normal growth and normal resting energy expenditure. A review of 35 children showed an average weight increase of only 0.44 kg/yr, beginning at 24 mo of age and persisting through life. There is interpatient variation in weight gain, but the projected weight gain over time in individual patients is constant, linear, and very predictable; this sharply contrasts with the parabolic growth pattern for normal age- and gender-matched children. Children reach an average final height of approximately 1 meter and weight of approximately 15 kg. Head circumference is normal. The weight deficit is more pronounced than the height deficit and, associated with the loss of subcutaneous fat, results in the emaciated appearance characteristic of progeria. Clinical problems caused by the lack of subcutaneous fat include sensitivity to cold temperatures and foot discomfort caused by lack of fat cushioning. Overt diabetes is very unusual in progeria, but about 30–40% of children have insulin resistance.

Ocular Abnormalities

Ophthalmic signs and symptoms are caused in part by tightened skin and a paucity of subcutaneous fat around the eyes. Children often experience hyperopia and signs of ocular surface disease from nocturnal lagophthalmos and exposure keratopathy, which in turn may lead to corneal ulceration and scarring. Some degree of photophobia is common. Most patients have relatively good acuity; however, advanced ophthalmic disease can be associated with reduced acuity. Children with progeria should have an ophthalmic evaluation at diagnosis and at least yearly thereafter. Aggressive ocular surface lubrication is recommended, including the use of tape tarsorrhaphy at night.

Craniofacial and Dental Phenotypes

Children develop craniofacial disproportion, with micrognathia and retrognathia caused by mandibular hypoplasia. Typical oral and dental manifestations include hypodontia, delayed tooth eruption, severe dental crowding, ogival palatal arch, ankyloglossia, presence of median sagittal palatal fissure, and generalized gingival recession. Eruption may be delayed for many months, and primary teeth may persist for the duration of life. Secondary teeth are present but may or may not erupt. They sometimes erupt on the lingual and palatal surfaces of the mandibular and maxillary alveolar ridges, rather than in place of the primary incisors. In some, but not all cases, extracting primary teeth promotes movement of secondary teeth into place.

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