The symptoms of ZSD vary greatly from one individual to another. The specific number and severity of symptoms present in an individual are highly variable and affected individuals will not have all of the symptoms discussed below. The most severe forms are usually noticeable shortly after birth. Severely affected infants often have distinct craniofacial features, neurological deficits, progressive dysfunction of the liver and kidneys and usually develop life-threatening complications during the first year of life.
Children with milder forms of ZSD may not develop symptoms until later during infancy. Some of these children reach adolescence or adulthood although most have some degree of intellectual disability, Hearing loss and vision problems. Some have profound loss of muscle tone (Hypotonia or floppiness), but some learn to walk and speak. Some children with these milder forms of ZSD do not have any CranioFacial abnormalities or only very mild ones.
In extremely rare cases, affected individuals have gone undetected until older childhood or adulthood. These individuals have had only mild symptoms such as adult-onset Hearing loss or Vision problems and/or mild developmental delays.
Many symptoms of ZSD are present at birth (congenital). Affected infants often exhibit prenatal Growth failure in spite of a normal period of gestation and may also have a profound lack of muscle tone (Hypotonia or floppiness). Affected infants may be limp, show little movement (lethargic) and poorly respond to environmental stimuli. Infants may be unable to suck and/or swallow leading to feeding difficulties and failure to gain weight and grow as expected (failure to thrive).
Infants may also develop a variety of neurological complications including frequent seizures, poor or absent reflexes, intellectual disability, and delays in reAching developmental milestones such as sitting, crawling or walking (developmental delays). Affected infants have various brain abnormalities including defects caused by the abnormal migration of brain cells (neurons). Neurons are created in the center of the developing brain and must travel to other areas of the brain to function properly. In individuals with ZSD, the neurons fail to migrate properly resulting in a variety of brain abnormalities (neuronal migration defects). Some affected infants also develop progressive Degeneration of the nerve fibers (white matter) of the brain (leukodystrophy).
Infants may have Distinctive facial features including a flattened appearance to the face, a high forehead, abnormally large “soft spots” (fontanelles) on the skull, broad bridge of the nose, a small nose with upturned nostrils (anteverted nares), an abnormally small jaw (micrognathia), a highly arched roof of the mouth (palate), a small chin, extra (redundant) folds of skin on the neck, and minor malformation of the outer part of the ears. The bony ridges of the eye socket may be abnormally shallow and the back of the head may be abnormally flat (flat occiput).
A variety of Eye abnormalities may occur including eyes that are spaced widely apart (hypertelorism), clouding of the lenses of the eyes (cataracts) or the clear (transparent) outer layer of the eye (corneal opacities), Degeneration of the nerve that carries visual images from the eye to the brain (optic atrophy), and rapid, involuntary eye movements (nystagmus). Many infants with ZSD develop Degeneration of the retina, which is the thin layer of nerve cells that sense light and convert it into nerve signals, which are then relayed to the brain through the optic nerve. Glaucoma, a condition characterized by increased pressure within the eye causing a distinctive pattern of visual impairment, may also occur. The various Eye abnormalities associated with ZSD can cause Loss of vision to varying degrees. In addition to vision loss, infants with ZSD also experience Hearing loss with onset during the first few months of life.
Some infants may have an abnormally Large spleen (splenomegaly) and/or liver (hepatomegaly). The liver may also be scarred (fibrotic) and inflamed (cirrhosis), with progressive loss of function resulting in a variety of symptoms such as yellowing of the skin and whites of the eyes (jaundice). Additional findings include small cysts on the kidneys and gastrointestinal bleeding due to deficiency of a coagulation factor in the blood. Some children may develop episodes of exaggerated or uncontrolled bleeding (hemorrhaging) including bleeding within the skull (intracranial bleeding). Eventually, liver failure may occur.
Minor skeletal abnormalities may also be present in ZSD including clubfoot, fingers that are fixed or stuck in a bent position and cannot extend or straighten fully (camptodactyly), and chondrodysplasia punctata, a condition characterized by the formation of small, hardened spots of calcium (stippling) on the knee cap (patella) and long bones of the arms and legs.
Certain Heart defects may also occur in infants with ZSD including septal defects and patent ductus arteriosus. Septal defects are “holes” in the heart, specifically holes in the thin partition (septum) that separates the chambers of the heart. Small septal defects may close on their own; larger defects may cause various symptoms including breathing irregularities and high blood pressure. Patent ductus arteriosus is a condition in which the two large arteries of the body (aorta and pulmonary artery) remain connected by a small blood vessel (ductus arteriosus) that is supposed to close after birth.
Due to the lack of muscle tone, laryngomalacia (floppy airway) and other respiratory problems may occur in infants with ZSD. Respiratory support may entail the use of a nasal cannula for oxygen to more aggressive forms of support as the disease progresses.
In some male infants with ZSD, additional symptoms may occur including the abnormal placement of the urinary opening on the underside of the penis (hypospadias) and failure of the testes to descend into the scrotum (cryptorchidism).
Intermediate/milder forms of ZSD may present in the newborn period or be detected by newborn screening, but generally come to attention later because of developmental delays and sensory impairment. The clinical course for ZSD is variable. Despite low tone, some may learn to walk, speak and achieve some developmental milestones. Some develop adrenal insufficiency, osteopenia, or Seizures over time. Teeth eruption is often delayed, and individuals often have tooth enamel abnormalities in their secondary teeth. Disease progression is often attributed to a leukodystrophy, or progressive Degeneration of myelin in the central nervous system, which often results in loss of skills and untimely death.
Even milder forms of ZSD present with primarily sensory impairment and little to no developmental delay.