Symptoms
Hypoplasia of the exocrine pancreas is a congenital developmental defect, affecting the part of the pancreas that produces digestive enzymes.
It creates pancreatic insufficiency, resulting in major impairment of digestion and affecting absorption of food.
This defect tends to become less pronounced as the child grows, making clinical identification of SDS particularly challenging in older
subjects unless sophisticated diagnostic tests are available.
Bone marrow dysfunctions are very varied. Marrow, overall development of which is insufficient, is replaced in part by fatty tissue:
this anomaly hinders production of red cells, platelets and the white cells known as neutrophil granulocytes, which normally form the first
line of defence against bacteria.
The most frequent defect is neutropaenia, a low neutrophil count, which can be steady-state (always present) but is more often intermittent (meaning that it comes and goes, with no predictable pattern).
In addition, the condition generally makes neutrophils sluggish and slows down their arrival at sites of infection.
This reduction in the neutrophil count and in their mobility favours infections, especially in very young children, causing earache,
bronchopneumonia, osteomyelitis, skin infections and septicaemia.
Thrombocytopaenia (a low blood platelet count) and anaemia (a decrease in red blood cells) occur less frequently.
In very young children, foetal haemoglobin levels are high.
In some cases (frequency still not clearly defined, but low in Italy), myeloproliferation can occur: this means involvement of the bone marrow,
with a tendency to develop myelodysplasia or leukaemia - above all, acute myeloid leukaemia.
Short stature is almost always present from birth and is not amenable to correction, even if growth rate is regular.
While bone disorders can be of different types, these are mainly structural alterations affecting the growth plates of large joints (metaphyseal dysplasia of the knee, elbow and hip) or the ribs (narrow rib cage). Valgus knee ("knock knees") can also be present. These alterations, which might be only partly reponsible for the stature deficit, tend to normalise only to a limited degree with age.
Associated anomalies
SDS can be associated with a number of other anomalies, varying greatly on a case by case basis:
liver dysfunctions (above all high transaminase levels and enlarged liver in the first few years of life);
diabetes mellitus;
deafness and defective eyesight;
retarded psychomotor development (quite frequent, though generally moderate, with some learning difficulties);
kidney complications;
ichthyosis;
poor tooth development (above all tooth enamel defects);
megacolon;
low immunoglobulin.
Causes
When both parents are healthy carriers of the specific gene mutation concerned, every child conceived by them has a 1 in 4 risk of being born with SDS. This is what is referred to as an autosomal recessive genetic disease. To put it more simply:
autosomal means that the gene involved is found in the "autosomes" - in other words, the non-sexual chromosomes (X or Y);
recessive indicates that the altered gene must be received from both parents for the disease to be present.
The gene responsible for SDS has been identified: localised at the start of the long arm of chromosome 7, it is known as SBDS.
Research has also identified various mutations of this gene - meaning alterations of its DNA that can lead to disease. In the most frequent
of these alterations, sections of DNA on the gene are substituted by sequences from a closely related (but difficult, or impossible, to define)
"pseudogene". The DNA sequences resulting from this insertion of incorrect material (a process known as gene conversion) create a truncated protein, which is unable to function properly and is quickly removed.
We still know relatively little about the protein produced by the SBDS gene, though it is thought to play an indispensable role in the
metabolism of RNA (the nucleic acid that receives from the DNA of the genes the information for the synthesis of proteins). The gene's ability
to function normally is an indispensable condition for development of the exocrine pancreas, of the bone marrow cells that give rise to blood
cells, as well as of cartilage and bone.
Treatment
Our knowledge of SDS still limits treatment to addressing the symptoms, not the underlying condition:
pancreatic insufficiency is treated by daily doses of pancreatic extracts, compensating for the insufficient secretion of pancreatic enzymes and allowing assimilation of food;
in some cases, vitamin A, D and E supplementation may be necessary;
infections have to be treated quickly and decisively;
all possible vaccinations should be given early;
more severe conditions of neutropaenia are today treated, though still on an experimental basis, with specific stimulating factors to promote development and maturation of bone marrow cells;
when genetic predisposition actually results in onset of leukaemia, a bone marrow stem cell transplant is needed.
Diagnosis
A possible diagnosis of SDS should never be overlooked in the following conditions:
all children showing low weight and short stature at birth, even if not born prematurely;
all children showing physical growth retardment by comparison with their age group;
all children with poor intestinal function and large, fatty stools;
all children with neutropaenia, whether or not this is associated with anaemia and a low platelet count;
in adolescents and adults with otherwise unexplained short stature and neutropaenia: in these age groups, symptoms related to pancreatic insufficiency can be absent or relatively difficult to spot.
Correct diagnosis is possible thanks to various direct or indirect tests of pancreatic function, blood tests (red and white cells, platelets) and skeletal X-rays. There must also be a negative sweat test, to exclude a diagnosis of cystic fibrosis (given the possible similarity between the two conditions).
Frequency
The exact incidence of SDS is unknown, but low.
Estimates vary a lot: from 1/10,000 to 1/200,000 live births.
In Italy, we are aware of 145 cases whose details are in the National Schwachman-Diamond Syndrome Registry.
Many other cases certainly continue to escape diagnosis (which still tends to prove difficult).
