Congenital hyperinsulinism
Encyclopedia
Congenital hyperinsulinism is a medical term referring to a variety of congenital disorder
s in which hypoglycemia
is caused by excessive insulin
secretion. Congenital forms of hyperinsulinemic hypoglycemia
can be transient or persistent, mild or severe. These conditions are present at birth and most become apparent in early infancy. The severe forms can cause obvious problems in the first hour of life, but milder forms may not be detected until adult years.
Mild cases can be treated by frequent feedings, more severe cases can be controlled by medications that reduce insulin secretion or effects, and a minority of the most severe cases require surgical removal of part or most of the pancreas
to protect the brain from damage due to recurrent hypoglycemia.
and islet cell adenomatosis were favored in the 1970s, beta cell dysregulation syndrome or dysmaturation syndrome in the 1980s, and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) in the 1990s.
, unresponsiveness, hypothermia
, or seizure
s. The most severe forms may cause macrosomia in utero, producing a large-for-gestational-age birth weight, often accompanied by enlargement of the heart
and liver
. Milder hypoglycemia in infancy causes hunger every few hours, with increasing irritability or lethargy if feeding is delayed.
Congenital hyperinsulinism often becomes apparent later in the first year of life, sometimes by a failure to tolerate increasing feeding intervals and an inability to sleep through the night. Sometimes an unusual stress like an illness precipitates a severe hypoglycemic episode.
Milder forms have occasionally been detected by investigation of family members of infants with severe forms. Adults with the mildest degrees of congenital hyperinsulinism may simply have a decreased tolerance for prolonged fasting.
The variable ages of presentations and courses suggest that some forms of congenital hyperinsulinism, especially those involving abnormalities of KATP channel function, can gradually worsen or improve with time.
The potential harm from hyperinsulinemic hypoglycemia appears to depend on the severity, frequency, and duration. Children who have prolonged or recurrent hyperinsulinemic hypoglycemia in infancy can suffer harm to their brain
s and may be developmentally delayed.
and ketone
s provide additional evidence of insulin excess. If this critical cannot be obtained during an early episode of spontaneous hypoglycemia, a diagnostic fast may be required.
An additional piece of evidence indicating hyperinsulinism is a usually high requirement for intravenous glucose to maintain adequate glucose levels. The minimum glucose required to maintain a plasma glucose above 70 mg/dl is referred to as the glucose infusion rate. A GIR above 8 mg/kg/minute in infancy suggests hyperinsulinism. A third form of evidence suggesting hyperinsulinism is a rise of the glucose level after injection of glucagon
at the time of the low glucose.
Once the evidence indicates hyperinsulinism, the diagnostic efforts shift to determining the type. Elevated ammonia
levels or abnormal organic acids can indicate specific, rare types. Intrauterine growth retardation and other perinatal problems raise the possibility of transience, while large birthweight suggests one of the more persistent conditions. Evidence for specific type can include responsiveness to some of the therapeutic measures. Gene
tic screening is now available within a useful time frame for some of the specific conditions.
It is usually worthwhile to identify the minority of severe cases with focal forms of hyperinsulinism because these can be completely cured by partial pancreatectomy. A variety of pre-operative diagnostic procedures have been investigated but none has been established as infallibly reliable. Positron emission tomography
(PET scanning) is becoming the most useful imaging technique and usually indicates whether the entire pancreas is producing too much insulin or whether a focal area is to blame.
Each treatment has its limitations and disadvantages or hazards. Many of the treatments do not effectively maintain a satisfactory blood glucose in the more severe cases. Many of the treatments aggravate the poor feeding behavior that often accompanies severe congenital hyperinsulinism. It is hard for parents to continue frequent feedings for many months. Increased calories and corn starch may produce excessive weight gain. Unexpected interruptions of continuous feeding regimens can result in sudden, severe hypoglycemia. Insertion and maintenance of nasogastric tubes is distasteful to parents. Gastrostomy tube insertion requires a minor surgical
procedure. Prolonged glucocorticoid use incurs the many unpleasant side effects of Cushing's syndrome
. Diazoxide can cause fluid retention requiring concomitant use of a diuretic
, and prolonged use causes hypertrichosis
. Diazoxide works by opening the KATP channels of the beta cell
s, and many of the Kir and SUR mutations are unresponsive. Octreotide must be given by injection several times a day or a subcutaneous pump must be inserted every few days. Octreotide can cause abdominal
discomfort and responsiveness to octreotide often wanes over time. Glucagon requires continuous intravenous infusion, incurring the infection
and blood clot hazards of prolonged central venous lines. Nifedipine is effective only in a minority, and dose is often limited by hypotension
.
Pancreatectomy (removal of a portion or nearly all of the pancreas
) is usually a treatment of last resort when the simpler medical measures fail to provide prolonged normal blood sugar levels. For many decades, the most common surgical procedure was removal of about 95% of the pancreas. This cured some infants but not all, and some needed second procedures to remove even the last remnants. Insulin-dependent diabetes mellitus
commonly develops, though in many cases it occurs many years after the pancreatectomy.
In the early 1990s it was discovered that a sizeable minority of cases of Kir and SUR mutations were focal, involving overproduction of insulin by only a portion of the pancreas. These cases can be cured by removing much less of the pancreas, resulting in excellent outcomes with no long-term problems. The initial pancreatectomy became a prolonged process of repeated microscopic
examination of small pieces removed from various parts of the pancreas while the infant was under anesthesia
in the operating room, with an experienced surgeon and pathologist
attempting to identify a focal region of overactive cells which could be completely removed.
The relative rarity of this condition and the difficulty of both diagnosis and treatment has resulted in only a few centers around the world developing the expertise to achieve optimal surgical outcomes for these infants: the Children's Hospital of Philadelphia
, the Great Ormond Street Hospital for Children
in London
, as well as centers in Paris
and Israel
.
Congenital disorder
A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation...
s in which hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
is caused by excessive insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
secretion. Congenital forms of hyperinsulinemic hypoglycemia
Hyperinsulinemic hypoglycemia
Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.-Causes:...
can be transient or persistent, mild or severe. These conditions are present at birth and most become apparent in early infancy. The severe forms can cause obvious problems in the first hour of life, but milder forms may not be detected until adult years.
Mild cases can be treated by frequent feedings, more severe cases can be controlled by medications that reduce insulin secretion or effects, and a minority of the most severe cases require surgical removal of part or most of the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
to protect the brain from damage due to recurrent hypoglycemia.
Terminology
This condition has been referred to by a variety of names in the past 50 years. NesidioblastosisNesidioblastosis
Nesidioblastosis is beta cell hyperplasia, consisting of the proliferation of islet cells from pancreatic ducts. It is a cause of hypoglycemia and hyperinsulinemia in a number of infants and newborns. Recently, this condition has been recognized in adolescents and adults and occurs in 5% of...
and islet cell adenomatosis were favored in the 1970s, beta cell dysregulation syndrome or dysmaturation syndrome in the 1980s, and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) in the 1990s.
Types of congenital hyperinsulinism
- Transient neonatal hyperinsulinism
- Focal hyperinsulinism
- Paternal SUR1 mutationMutationIn molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
with clonal loss of heterozygosity of 11p15 - Paternal Kir6.2Kir6.2Kir6.2 is a major subunit of the ATP-sensitive K+ channel, an inward-rectifier potassium ion channel. The gene encoding the channel is called KCNJ11 and mutations in this gene are associated with congenital hyperinsulinism.-Structure:...
mutation with clonal loss of heterozygosity of 11p15
- Paternal SUR1 mutation
- Diffuse hyperinsulinism
- Autosomal recessive forms
- SUR1 mutations
- Kir6.2 mutations
- Congenital disorders of glycosylation
- Autosomal dominant forms
- GlucokinaseGlucokinaseGlucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver, pancreas, gut, and brain of humans and most other vertebrates...
gain-of-function mutations - HyperammonemicHyperammonemiaHyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to encephalopathy and death. It may be primary or secondary....
hyperinsulinism (glutamate dehydrogenase gain-of-function mutations) - Short chain acyl coenzyme A dehydrogenase deficiency
- Glucokinase
- Autosomal recessive forms
- Beckwith-Wiedemann syndromeBeckwith-Wiedemann syndromeBeckwith–Wiedemann syndrome is an overgrowth disorder usually present at birth characterized by an increased risk of childhood cancer and certain congenital features. Originally, Dr...
(thought to be due to hyperinsulinism but pathophysiology still uncertain: 11p15 mutation or IGF2 excess)
Common presentations and natural history
Manifestations of congenital hyperinsulinemic hypoglycemia vary by age and severity of the hypoglycemia. Hypoglycemia in early infancy can cause jitteriness, lethargy, cyanosisCyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
, unresponsiveness, hypothermia
Hypothermia
Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
, or seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s. The most severe forms may cause macrosomia in utero, producing a large-for-gestational-age birth weight, often accompanied by enlargement of the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
and liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. Milder hypoglycemia in infancy causes hunger every few hours, with increasing irritability or lethargy if feeding is delayed.
Congenital hyperinsulinism often becomes apparent later in the first year of life, sometimes by a failure to tolerate increasing feeding intervals and an inability to sleep through the night. Sometimes an unusual stress like an illness precipitates a severe hypoglycemic episode.
Milder forms have occasionally been detected by investigation of family members of infants with severe forms. Adults with the mildest degrees of congenital hyperinsulinism may simply have a decreased tolerance for prolonged fasting.
The variable ages of presentations and courses suggest that some forms of congenital hyperinsulinism, especially those involving abnormalities of KATP channel function, can gradually worsen or improve with time.
The potential harm from hyperinsulinemic hypoglycemia appears to depend on the severity, frequency, and duration. Children who have prolonged or recurrent hyperinsulinemic hypoglycemia in infancy can suffer harm to their brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
s and may be developmentally delayed.
Diagnostic evaluation
When the cause of hypoglycemia is not obvious, the most valuable diagnostic information is obtained from a blood sample drawn during the hypoglycemia. Detectable amounts of insulin during hypoglycemia are abnormal and indicate that hyperinsulinism is likely to be the cause. Inappropriately low levels of free fatty acids, beta-hydroxybutyrateBeta-hydroxybutyrate
beta-Hydroxybutyric acid is a ketone body. It is a chiral compound having two enantiomers, D-3-hydroxybutyric acid and L-3-hydroxybutyric acid. Like the other ketone bodies , levels of beta-hydroxybutyrate are raised in ketosis...
and ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
s provide additional evidence of insulin excess. If this critical cannot be obtained during an early episode of spontaneous hypoglycemia, a diagnostic fast may be required.
An additional piece of evidence indicating hyperinsulinism is a usually high requirement for intravenous glucose to maintain adequate glucose levels. The minimum glucose required to maintain a plasma glucose above 70 mg/dl is referred to as the glucose infusion rate. A GIR above 8 mg/kg/minute in infancy suggests hyperinsulinism. A third form of evidence suggesting hyperinsulinism is a rise of the glucose level after injection of glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
at the time of the low glucose.
Once the evidence indicates hyperinsulinism, the diagnostic efforts shift to determining the type. Elevated ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
levels or abnormal organic acids can indicate specific, rare types. Intrauterine growth retardation and other perinatal problems raise the possibility of transience, while large birthweight suggests one of the more persistent conditions. Evidence for specific type can include responsiveness to some of the therapeutic measures. Gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
tic screening is now available within a useful time frame for some of the specific conditions.
It is usually worthwhile to identify the minority of severe cases with focal forms of hyperinsulinism because these can be completely cured by partial pancreatectomy. A variety of pre-operative diagnostic procedures have been investigated but none has been established as infallibly reliable. Positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET scanning) is becoming the most useful imaging technique and usually indicates whether the entire pancreas is producing too much insulin or whether a focal area is to blame.
Treatment
Acute hypoglycemia is immediately reversed by raising the blood glucose, but in most forms of congenital hyperinsulinism hypoglycemia recurs and the therapeutic effort is directed toward preventing falls and maintaining a glucose above 70 mg/dl (3.9 mM). Some of the following measures are often tried:- shorter feeding interval (every 2 hours)
- increased calorie density of formula (usually 24 calories per ounce instead of 20)
- continuous feeding with formulaInfant formulaInfant formula is a manufactured food designed and marketed for feeding to babies and infants under 12 months of age, usually prepared for bottle-feeding or cup-feeding from powder or liquid . The U.S...
through a nasogastric tube or gastrostomyGastrostomyGastrostomy refers to a surgical opening into the stomach. Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression....
, sometimes with added corn starch - continuous intravenous dextrose
- hydrocortisone or other glucocorticoidGlucocorticoidGlucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
- diazoxideDiazoxideDiazoxide is a potassium channel activator, which causes local relaxation in smooth muscle by increasing membrane permeability to potassium ions...
by mouth - octreotideOctreotideOctreotide is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone...
(a somatostatinSomatostatinSomatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
analog) by subcutaneous injection or infusion - glucagonGlucagonGlucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
by continuous intravenous infusion - nifedipineNifedipineNifedipine is a dihydropyridine calcium channel blocker...
or other calcium channel blockerCalcium channel blockerA calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with... - partial pancreatectomyPancreatectomyIn medicine, a pancreatectomy is the surgical removal of all or part of the pancreas. Several types of pancreatectomy exist, including pancreaticoduodenectomy , distal pancreatectomy, segmental pancreatectomy, and total pancreatectomy...
Each treatment has its limitations and disadvantages or hazards. Many of the treatments do not effectively maintain a satisfactory blood glucose in the more severe cases. Many of the treatments aggravate the poor feeding behavior that often accompanies severe congenital hyperinsulinism. It is hard for parents to continue frequent feedings for many months. Increased calories and corn starch may produce excessive weight gain. Unexpected interruptions of continuous feeding regimens can result in sudden, severe hypoglycemia. Insertion and maintenance of nasogastric tubes is distasteful to parents. Gastrostomy tube insertion requires a minor surgical
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
procedure. Prolonged glucocorticoid use incurs the many unpleasant side effects of Cushing's syndrome
Cushing's syndrome
Cushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...
. Diazoxide can cause fluid retention requiring concomitant use of a diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
, and prolonged use causes hypertrichosis
Hypertrichosis
Hypertrichosis is an abnormal amount of hair growth on the body; extensive cases of hypertrichosis have informally been called werewolf syndrome. There are two distinct types of hypertrichosis: generalized hypertrichosis, which occurs over the entire body, and localized hypertrichosis, which is...
. Diazoxide works by opening the KATP channels of the beta cell
Beta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...
s, and many of the Kir and SUR mutations are unresponsive. Octreotide must be given by injection several times a day or a subcutaneous pump must be inserted every few days. Octreotide can cause abdominal
Abdomen
In vertebrates such as mammals the abdomen constitutes the part of the body between the thorax and pelvis. The region enclosed by the abdomen is termed the abdominal cavity...
discomfort and responsiveness to octreotide often wanes over time. Glucagon requires continuous intravenous infusion, incurring the infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
and blood clot hazards of prolonged central venous lines. Nifedipine is effective only in a minority, and dose is often limited by hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
.
Pancreatectomy (removal of a portion or nearly all of the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
) is usually a treatment of last resort when the simpler medical measures fail to provide prolonged normal blood sugar levels. For many decades, the most common surgical procedure was removal of about 95% of the pancreas. This cured some infants but not all, and some needed second procedures to remove even the last remnants. Insulin-dependent diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
commonly develops, though in many cases it occurs many years after the pancreatectomy.
In the early 1990s it was discovered that a sizeable minority of cases of Kir and SUR mutations were focal, involving overproduction of insulin by only a portion of the pancreas. These cases can be cured by removing much less of the pancreas, resulting in excellent outcomes with no long-term problems. The initial pancreatectomy became a prolonged process of repeated microscopic
Microscope
A microscope is an instrument used to see objects that are too small for the naked eye. The science of investigating small objects using such an instrument is called microscopy...
examination of small pieces removed from various parts of the pancreas while the infant was under anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
in the operating room, with an experienced surgeon and pathologist
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
attempting to identify a focal region of overactive cells which could be completely removed.
The relative rarity of this condition and the difficulty of both diagnosis and treatment has resulted in only a few centers around the world developing the expertise to achieve optimal surgical outcomes for these infants: the Children's Hospital of Philadelphia
Children's Hospital of Philadelphia
The Children's Hospital of Philadelphia is one of the largest and oldest children's hospitals in the world. CHOP has been ranked as the best children's hospital in the United States by U.S. News & World Report and Parents Magazine in recent years. As of 2008, it was ranked #1 in the nation for...
, the Great Ormond Street Hospital for Children
Great Ormond Street Hospital
Great Ormond Street Hospital for Children is a children's hospital located in London, United Kingdom...
in London
London
London is the capital city of :England and the :United Kingdom, the largest metropolitan area in the United Kingdom, and the largest urban zone in the European Union by most measures. Located on the River Thames, London has been a major settlement for two millennia, its history going back to its...
, as well as centers in Paris
Paris
Paris is the capital and largest city in France, situated on the river Seine, in northern France, at the heart of the Île-de-France region...
and Israel
Israel
The State of Israel is a parliamentary republic located in the Middle East, along the eastern shore of the Mediterranean Sea...
.
External links
- GeneReviews/NIH/NCBI/UW entry on Familial Hyperinsulinism (FHI)
- Congenital Hyperinsulinism Center @ Children's Hospital of Philadelphia
- Sur1 Hyperinsulinism Website for families of children with hyperinsulinism.
- Congenital Hyperinsulinism International (CHI) A charitable organization dedicated to improving the lives of children, adults, and families living with congenital hyperinsulinism.
- The Children's Hyperinsulinism Fund The Children's Hyperinsulinism Fund helps children in the UK and around the world who suffer from Congenital Hyperinsulinism.
- Netzwerk für Eltern von Kindern mit Hyperinsulinismus
- Collaborative Alliance for Congenital Hyperinsulinism
- Homepage of the Clinic for Pediatric Surgery, Universitymedicine Greifswald