The symptoms and onset of symptoms in patients with dyskeratosis congenita varies greatly depending on the gene mutated, the nature of the mutation, for how many generations the mutation has been inherited, and possibly other genetic and environmental factors. However, even among members of the same family the symptoms and onset may vary to some degree. In some families disease seems to become more severe and manifests earlier in life with subsequent generations. One of the characteristics is that, with the exception of the very severe forms (Hoyeraal-Hreidarsson and to some extent the Revesz syndrome), clinical symptoms are not present at birth, but develop during childhood, adolescence, and in some cases only late in life. In general, the earlier the disease becomes apparent, the more likely it is that the disease is severe and rapidly progressing. Likewise, the later in life clinical symptoms appear, the milder the form of disease and the slower the progression of disease. The exception to this is the risk of cancer and leukemia, which increases with age and is more common in patients with moderate to mild forms of disease. Patients with the classic form of dyskeratosis congenita are those who present with the originally described skin, nail and mouth abnormalities. In these patients the skin and nail abnormalities usually appear before 10 years of age and bone marrow failure by 20 years of age. In approximately 80-90 percent of patients with classic dyskeratosis congenita bone marrow failure occurs by age 30. In some cases, bone marrow failure appears before skin, nail or mucous membrane symptoms. Patients with the mild form of dyskeratosis congenita may have no apparent symptoms (asymptomatic) into their 30s or 40s and often present only with one of the clinical features associated with dyskeratosis congenita such as bone marrow failure, pulmonary fibrosis, liver fibrosis, or osteoporosis. Skin and nail changes, might be so mild that they are overlooked, or not noticed.
The X-linked form and some of the sporadic forms often present as classic dyskeratosis congenita, whereas individuals with the autosomal dominant form of dyskeratosis congenita often tend to have fewer abnormalities and later onset of symptoms. The skin and mucous membranes abnormalities are usually milder in the autosomal dominant form. The autosomal recessive form can vary dramatically with some individuals experiencing bone marrow failure early during childhood, while others have no blood abnormalities into their 40s. Although these findings are typical of many cases, individual cases may turn out differently.
Skin, nail, and mouth changes
The skin abnormalities associated with dyskeratosis congenita include abnormal dark discoloration of the skin with a distribution pattern that resembles a net (reticulate hyperpigmentation). Affected areas may appear as grayish, flat spots (macules) on a degenerated (atrophic) or light colored patch of skin. The face, neck and shoulders are most often affected.
Nail abnormalities usually affect the fingernails before the toenails and are characterized by fissures, underdevelopment (hypoplasia) and eventually degeneration and distortion of the affected nails. Some individuals may ultimately lose the affected nails.
The development of white, thickened patches on mucous membranes of the mouth (oral leukoplakia) usually develops slowly appearing anywhere during the second, third or fourth decade. Although the mouth is predominantly affected, the mucous membranes of the anus and the urethra may become involved in rare cases.
Bone marrow failure
Most individuals with dyskeratosis congenita eventually develop bone marrow failure marked by deficiency of all three of the main types of blood cells (i.e., red cells, white cells, and platelets) a condition called pancytopenia. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections, and platelets allow the body to form clots to stop bleeding. The degree of bone marrow failure can greatly vary from very mild with only one type of blood cell affected to very severe with low counts in all blood cell lineages. Bone marrow examination shows a reduced number of blood cell producing progenitor cells (hyopcelular or empty bone marrow). Sometimes it is not only the blood counts that are abnormal but the blood cells themselves can show abnormalities, such as chromosomal (karyotypic) differences. These findings are usually described as myelodysplasia or myelodysplastic syndrome (MDS). Patients with MDS are at a higher risk of developing leukemia particularly if they are associated with certain karyotypic abnormities such as only one chromosome 7 (monosomy 7) over a long period of time. In rare cases MDS or leukemia may be the first manifestation of disease.
Pancytopenia (low blood cell count of all blood cell lineages) may result in a variety of symptoms. Bruising, small red spots on the skin (petechiae), paleness of the skin (pallor) and Frequent infections may be the first signs of bone marrow failure. The specific symptoms and progression of the disorder vary from case to case. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to life-threatening complications. Bone marrow failure may develop during childhood or not become severe until well into adulthood.
Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, Pale skin color, difficulty breathing (dyspnea), and cardiac symptoms. Individuals with low white blood cell counts (leukopenia) have an increased risk of contracting bacterial and fungal infections. Individuals with low platelet counts (thrombocytopenia) are more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose.
Some patients with the same genetic abnormality responsible for dyskeratosis congenita may present with bone marrow failure only. The severity of bone marrow failure in these patients can vary greatly, from affecting only one or two blood values in peripheral blood, to the full picture with low blood counts in all blood cell lineages, a condition termed aplastic anemia. Features of the skin or other symptoms associated with dyskeratosis congenita may not be present or be so mild that they are not appreciated. These patients are often initially misdiagnosed as having idiopathic aplastic anemia (see also below). Whether patients with the genetic abnormality for dyskeratosis congenita but only showing bone marrow failure should be classified as having dyskeratosis congenita is controversial, alternative classifications used are atypical dyskeratosis congenita, or aplastic anemia with short telomeres. It is important that in these individuals the treatment plan, response to treatment, disease surveillance, and prognosis differs from patients with idiopathic aplastic anemia. In addition because of the inherited nature of the disease, members of the family of the affected individual may also be at risk.
Leukemia and cancer
Individuals with dyskeratosis congenita also have a predisposition to develop leukemia and cancer (malignancy) especially squamous cell carcinoma of the head and neck, and especially at the site of leukoplakia. If cancer occurs, it usually does not develop until the age of about 30. Thus, leukemia and cancer are more common in individuals who have a moderate or milder form of dyskeratosis congenita. Individuals who underwent a stem cell or bone marrow transplant for the treatment of their bone marrow failure are also at risk of developing cancer later in life. In rare cases leukemia or cancer may be the first manifestation of disease.
The development of lung disease (pulmonary fibrosis) is often found in patients with dyskeratosis congenita. It usually develops later than the skin abnormalities and bone marrow failure, however in some patients with mild disease pulmonary fibrosis may be the first or only obvious manifestation. In these patients disease usually manifest at the age of 50 to 60 years of age. The cause of pulmonary fibrosis in patients with dyskeratosis congenita is not fully understood. Breathing difficulties and a decreased lung function may be signs of lung disease. Smoking seems to accelerate the progression of pulmonary disease.
A variety of additional symptoms have been reported in individuals with dyskeratosis congenita. These symptoms occur with much less frequency than the abovementioned symptoms. These less common symptoms include excessively watery eyes due to obstruction of the tear ducts (epiphora), excessive sweating (hyperhidrosis) of the palms of the hands and the soles of the feet, cavities and tooth loss, narrowing of the esophagus (esophageal stricture), urinary tract anomalies, especially hypospadism, early graying and premature hair loss, lung disease and short stature, liver disease, underdeveloped testes (hypogonadism), failure of the testes to descend into the scrotum, and skeletal abnormalities.
Some affected children may experience delays in attaining developmental milestones and learning disabilities. Additional symptoms have been reported that occur in less than 10 percent of cases including deafness, or abnormalities of the eye retina.
Once considered a separate disorder, Hoyeraal-Hreidarsson syndrome is now identified as a severe variant of dyskeratosis congenita. Symptoms usually occur during the first year of life and include severe growth retardation that occurs before birth (intrauterine growth retardation), bone marrow failure, immune system deficiencies, underdevelopment of the cerebellum (cerebellar hypoplasia), clumsiness caused by the inability to coordinate voluntary movements (ataxia), and microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant’s age and sex. Abnormalities of the gut varying from malabsorbtion to severe Inflammation with ulcers may be present in these children. Bone marrow failure and immune system deficiency may result in life-threatening complications. Because of the complexity and because multiple organs are severely impaired the prognosis of children diagnosed with Hoyeraal-Hreidarsson syndrome is usually poor. These children often die before they develop the characteristic nail and skin abnormalities.
Revesz syndrome is another severe form of dyskeratosis congenita that may present similar to the Hoyeraal-Hreidarsson syndrome but in addition is associated with abnormalities of the eye (bilateral exudative retinopathy, Coats retinopathy).